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.

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.

Effects of missed dose and delayed dose quetiapine on its pharmacokinetics and pharmacodynamics.

AIM OF THE STUDY: Nonadherence to the prescribed medication can result in a poor treatment outcome. This study determined the impacts of multiple missed dose or delayed dose scenarios on quetiapine (QTP) pharmacokinetics and pharmacodynamics. METHODS: QTP concentration-time profiles and Brief Psychiatric Rating Scale (BPRS) scores under multiple missed doses and delayed dose scenarios were simulated using Monte Carlo simulations and compared with those of the full adherence scenario using the Mann-Whitney U test. The simulations were performed using the model structure and parameter estimates obtained from Kimko et al's study. RESULTS: Missing one, two and three consecutive QTP doses significantly decreased trough concentration (Ctrough) by 71.4, 103, and 128ng/mL. However, Ctrough rapidly increased to values close to those of the full adherence scenario when the regular dose was resumed. Further, all missed dose scenarios did not significantly impact the maximum percent reduction of BPRS score from baseline, but significant impacts on the minimum percent reduction of BPRS score from baseline were observed. However, the change in BPRS score from the full adherence scenario rapidly resumed when the regular dose was taken. Moreover, this study identified that a delayed dose as late as 6 hours did not significantly impact the maximum concentrations when the regular dose was resumed. CONCLUSION: Based on the simulations, a missed dose can be taken as late as 6 hours before the next scheduled dose, otherwise it should be skipped. For multiple missed doses scenarios, QTP pharmacokinetics and pharmacodynamics rapidly returned to the stage close to the full adherence scenario when a single regular dose was resumed.

The effect of nonadherence on phenobarbital concentrations and recommendations on the replacement dose using Monte Carlo simulation.

OBJECTIVES: To determine the impacts of missed phenobarbital (PB) doses on its pharmacokinetics and to investigate the appropriate replacement dosing scheme for various PB missed dose scenarios. METHODS: Monte Carlo simulations were performed using parameters from the selected population pharmacokinetic study. The impacts of missed PB dose and the proper replacement dosing scheme were assessed based on the percent deviation of simulated concentrations outside the reference range from the full adherence scenario. RESULTS: The impact of missed PB dose on its concentrations depended on the daily dose. The replacement with a respective regular dose and one and a half regular dose was appropriate for the one and two missed doses scenarios for patients receiving PB monotherapy. For patients receiving PB with valproic acid or phenytoin, the same replacement scheme was still appropriate. The results also indicated that weight did not influence the proper replacement dosing scheme. CONCLUSIONS: The impacts of missed PB doses on its pharmacokinetics were identified and the proper replacement dosing schemes for different missed dose scenarios were proposed. These schemes should be implemented based on the clinician's justification of the patient's seizure control.

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.

Simulations of topiramate dosage recommendations for poor compliance events.

PURPOSE: To determine the influences of one or two consecutive missed topiramate (TPM) doses on TPM pharmacokinetics and to suggest the proper TPM replacement dosing schemes using Monte Carlo simulations. METHODS: Monte Carlo simulations were performed for various replacement dosing schemes using the parameters from the published population pharmacokinetic models. The lowest percentage of deviation of simulated concentrations outside the reference range of 5-20 mg/L from the compliance scenario for each replacement dosing scheme was used as a criterion for choosing the proper replacement dosing scheme. RESULTS: For the one missed dose, the replacement with an immediate regular dose and a partial dose resulted in the lowest and highest percentages of concentration below 5 mg/L, respectively. While the opposite results were observed for the upper bound of the reference range (20 mg/L). For the two consecutive missed doses, the replacement with one and a half-missed doses resulted in a lower percentage of deviation of concentrations below 5 mg/L from the compliance scenario than the replacement with one regular dose. CONCLUSIONS: For the one missed dose, taking an immediate regular dose might be suitable for patients who require higher TPM levels, while for patients who require lower TPM levels, an immediate partial dose could be used. For the two consecutive missed doses, an immediate one and a half regular dose might be suitable. However, these results were merely based on simulations; thus, they should be used alongside the clinician's justification based on seizure control.

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.

Lithium replacement dose recommendations using Monte Carlo simulations.

OBJECTIVES: Missed medication doses are a common clinical problem, and cause consternation when prescribing lithium because its plasma levels must be kept within a narrow therapeutic window. Therefore, this study set out to determine the potential impact of missed lithium doses on its pharmacokinetics, and to explore the optimal compensatory dosing scheme. This is difficult to determine clinically and in research because of ethical constraints and therefore we modelled the effects using simulations. METHODS: Monte Carlo simulations were used to simulate lithium concentrations under different missed dose scenarios. For patients with normal renal function, the optimal replacement dosing scheme was selected based on the lowest percentage of deviation from the full adherence scenario. However, for patients with renal impairment the appropriate dosing schedule was selected based on the lowest number of simulated concentrations above the upper range of 1.2 mEq/L. RESULTS: The impact of a missed lithium dose depended on its daily dose. The higher the daily dose, the higher the deviation from full adherence. In patients with normal renal function, replacement with a regular dose was most appropriate. But in patients with renal impairment, replacement with a partial dose appeared to be most suitable. CONCLUSIONS: This study has enabled insights into the optimal suitable lithium replacement dosing schemes for patients with normal renal function and renal impairment. These proposed schemes can be used cautiously in clinical practice in conjunction with clinician judgment and can also be used as a basis for future clinical research.

The effect of nonadherence on phenobarbital concentrations and recommendations on the replacement dose using Monte Carlo simulation.

OBJECTIVES: To determine the impacts of missed phenobarbital (PB) doses on its pharmacokinetics and to investigate the appropriate replacement dosing scheme for various PB missed dose scenarios. METHODS: Monte Carlo simulations were performed using parameters from the selected population pharmacokinetic study. The impacts of missed PB dose and the proper replacement dosing scheme were assessed based on the percent deviation of simulated concentrations outside the reference range from the full adherence scenario. RESULTS: The impact of missed PB dose on its concentrations depended on the daily dose. The replacement with a respective regular dose and one and a half regular dose was appropriate for the one and two missed doses scenarios for patients receiving PB monotherapy. For patients receiving PB with valproic acid or phenytoin, the same replacement scheme was still appropriate. The results also indicated that weight did not influence the proper replacement dosing scheme. CONCLUSIONS: The impacts of missed PB doses on its pharmacokinetics were identified and the proper replacement dosing schemes for different missed dose scenarios were proposed. These schemes should be implemented based on the clinician's justification of the patient's seizure control.

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.

Effect of Nonadherence on Levetiracetam Pharmacokinetics and Remedial Dose Recommendations Using Monte Carlo Simulations.

BACKGROUND AND OBJECTIVE: Nonadherence to levetiracetam (LEV) use can result in subtherapeutic concentrations and increase the risk of the occurrence of seizures. The impact of missing LEV doses on its pharmacokinetics and evidence of the appropriate remedial dose is lacking. This study has determined the influence of missed LEV doses on its pharmacokinetics and has explored the appropriate remedial dosage regimens. METHODS: Monte Carlo simulation was used to assess the impacts of different remedial dosage regimens on LEV concentrations. Simulated LEV concentrations outside the individual therapeutic range were calculated for the compliance scenario and for each of the remedial dosage regimens. The percentage of deviation from the full compliance scenario was also calculated. The regimen with the lowest percentage of deviation was considered the most appropriate. RESULTS: The suitable LEV remedial dose varied across the delay times. For one missed dose, a remedial regimen with a regular dose followed by the usual dose was suitable for a delay time of less than 6 h, while a replacement with a regular dose followed by a partial dose appeared to be appropriate for a delay time of 6 h and longer. This was justified based on the concerns of LEV toxicity when the remedial dose is close to the next scheduled dose. For two consecutive missed doses, a remedial dose with one and a half of the regular dose was suitable if the gap between that and the next dose was greater than 6 h. CONCLUSIONS: The appropriate remedial dosage regimen for one and two consecutive missed doses of LEV have been proposed. These remedial regimens, however, should be applied with clinicians' judgment based on the clinical status of the patients.

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.

Comparison of area under the curve for vancomycin from one- and two-compartment models using sparse data.

BACKGROUND AND OBJECTIVE: Vancomycin pharmacokinetics have been described by both one- and two-compartment models. One-compartment models are widely used to predict the area under the curve (AUC), a useful parameter for determining the efficacy and safety of vancomycin, based on sparse data collected during therapeutic drug monitoring. It is uncertain whether AUCs from one-compartment models with sparsely sampled data can sufficiently represent the true AUC. This study aimed to compare AUC estimates from one- and two-compartment models using sparse data. The reliability of AUCs from models constructed with trough-only data was also assessed. METHODS: A previously published robust model was used to simulate vancomycin concentration points at 15 min intervals in 100 patients. From these simulated data, the reference AUC (AUCref) was calculated and two depleted dataset versions (trough-only and peak-trough datasets) were also created. One- and two-compartment models were built from the depleted datasets with the use of NONMEM. Vancomycin 24-hour AUC was calculated from concentration-time profiles of each model by a linear trapezoidal formula at three different time periods: 0-24 hours (AUC0-24), 24-48 hours (AUC24-48) and 0-48 hours (AUCavg). The deviation of each of the AUCs from the AUCref was examined to assess the AUC predictability of models from sparse data. The difference in AUCs between one- and two-compartment models was analysed from statistical and clinical perspectives. RESULTS: When assessing the deviation of each AUC from the AUCref, the one-compartment model from both peak-trough and trough-only data could adequately represent the true AUC with no statistically significant differences. Two-compartment model from peak-trough data also provided similar AUC estimates with the AUCref. However, AUCs from the two-compartment model with trough-only data did not adequately represent the true AUC, with significant differences of 25.16% for AUC0-24, 15.92% for AUC24-48 and 19.45% for AUCavg. CONCLUSION: Regardless of statistically significant differences between AUCs from one- and two-compartment models, the level of difference was acceptable from the clinical perspective, being <17% in models from peak-trough data. Therefore, both one- and two-compartment models with sparse data having at least a pair of peak-trough data per patient could be reliable for predicting AUC. Furthermore, AUCs of the one-compartment model from trough-only data did not show a significant difference from the AUCref. Hence, one-compartment models developed from trough-only data could be useful for predicting AUC when models with rich data are not available for the intended population. However, it is suggested that the use of the two-compartment model built from trough-only data should be avoided.

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.

Development of a Physiologically Based Pharmacokinetic Model of Mitragynine, Psychoactive Alkaloid in Kratom (Mitragyna Speciosa Korth.), In Rats and Humans.

Mitragynine is a major psychoactive alkaloid in leaves of kratom (Mitragyna speciosa Korth.). To understand its disposition in organs, this study aimed to develop a physiologically based pharmacokinetic (PBPK) model that predicts mitragynine concentrations in plasma and organ of interests in rats and humans. The PBPK model consisted of six organ compartments (i.e. lung, brain, liver, fat, slowly perfused tissues, and rapidly perfused tissue). From systematic searching, three pharmacokinetic studies of mitragynine (two studies in rats and 1 study in humans) were retrieved from the literature. Berkeley Madonna Software (version 8.3.18) was used for model development and model simulation. The developed PBPK model consisted of biologically relevant features following involvement of (i) breast cancer-resistant protein (BCRP) in brain, (ii) a hepatic cytochrome P450 3A4 (CYP3A4)-mediated metabolism in the liver, and (iii) a diffusion-limited transport in fat. The simulations adequately describe simulated and observed data in the two species with different dosing regimens. PBPK models of mitragynine in rats and humans were successfully developed. The models may be used to guide optimal mitragynine dosing regimens.

Drug-Related Problems Identified at Patients' Home: A Prospective Observational Study in a Rural Area of Thailand.

OBJECTIVE: The aim of the study was to examine the prevalence rates, nature, and predictors of drug-related problems (DRPs) experienced in participants living at home in a rural Thailand. METHOD: A cross-sectional observational study was undertaken during December 2015 to January 2016. Drug-related problems were identified within a rural township having a population of 5256 by means of home visits by pharmacists. All suspected cases were then assessed for severity and preventability by clinical specialists. Drug-related problems were categorized according to Pharmaceutical Care Network Europe classification (revised 2010).v.6.2. RESULTS: From a systematically recruited cohort of 359 participants, suspected DRPs were identified in 160 participants. After detailed reviews by clinical specialists, 141 cases (39.3%) were deemed to have DRPs. Types of DRPs with prevalence rates were the following: problems of treatment effectiveness (3.7% of DPRs), adverse reactions (15.3%), treatment cost (28.4%), nonadherence to drugs (42.1%), and poor drug storage (10.5%). The most common drug to involve DRPs was those treating cardiovascular disease, especially simvastatin. CONCLUSIONS: Nearly half of community living participants experienced DRPs, especially nonadherence to drugs, and has implications for other rural elderly persons of low education attainment for similar rural economies around the globe. Appropriate interventions should focus on reducing polypharmacy, providing outreach programs, and rigorous pharmacovigilance.