Population Pharmacokinetic Model of Intravenous Immunoglobulin in Patients Treated for Various Immune System Disorders.

PURPOSE: Intravenous immunoglobulin (IVIG) is used to treat various immune system disorders, but the factors influencing its disposition are not well understood. This study aimed to estimate the population pharmacokinetic parameters of IVIG and to investigate the effect of genetic polymorphism of the FCGRT gene encoding the neonatal Fc receptor (FcRn) and clinical variability on the pharmacokinetic properties of IVIG in patients with immune system disorders. METHODS: Patients were recruited from 4 hospitals in Malaysia. Clinical data were recorded, and blood samples were taken for pharmacokinetic and genetic studies. Population pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling in Monolix. Age, weight, baseline immunoglobulin G concentration, ethnicity, sex, genotype, disease type, and comorbidity were investigated as potential covariates. Models were evaluated using the difference in objective function value, goodness-of-fit plots, visual predictive checks, and bootstrap analysis. FINDINGS: A total of 292 blood samples were analyzed from 79 patients. The IVIG concentrations were best described by a 2-compartment model with linear elimination. Weight was found to be an important covariate for volume of distribution in the central compartment (Vc), volume of distribution in the peripheral compartment (Vp), and clearance in the central compartment, whereas disease type was found to be an important covariate for Vp. Goodness-of-fit plots indicated that the model fit the data adequately. Genetic polymorphism of the FCGRT gene encoding the neonatal Fc receptor did not affect the pharmacokinetic properties of IVIG. IMPLICATIONS: This study supports the use of dosage based on weight as per current practice. The study findings highlight that Vp is significantly influenced by the type of disease being treated with IVIG. This relationship suggests that different disease types, particularly inflammatory and autoimmune conditions, may alter tissue permeability and fluid distribution due to varying degrees of inflammation. Increased inflammation can lead to enhanced permeability and retention of IVIG in peripheral tissues, reflecting higher Vp values.

Therapeutic drug monitoring-guided piperacillin dosing in critically ill patients undergoing continuous renal replacement therapy: a systematic review.

BACKGROUND: Continuous renal replacement therapy (CRRT) complicates antibiotic dosing in critically ill patients due to altered pharmacokinetics. The optimal dosing of piperacillin remains unclear. Therapeutic drug monitoring (TDM) can personalize piperacillin therapy and improve outcomes. OBJECTIVES: This review investigates the effects of TDM-guided piperacillin dosing on pharmacokinetic target attainment and clinical outcomes in CRRT patients, analyses correlations with clinical outcomes, provides optimal dosing strategies for piperacillin and identifies future research areas. METHODS: A systematic search of PubMed, Scopus and Web of Science was conducted until December 2023, identifying studies on piperacillin pharmacokinetics and clinical outcomes in adult CRRT patients. Data on study characteristics, piperacillin exposures, TDM use, target attainment rates, mortality and length of stay were extracted. The risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: Eleven observational studies were included. High pharmacokinetic variability was evident, with piperacillin target non-attainment in up to 74% of cases without TDM. Two studies with routine TDM showed increased target attainment rates of 80%-100%. Mortality ranged from 17% to 56%, with supratherapeutic concentrations (≥100 mg/L) associated with higher mortality. The impact of optimized piperacillin exposures on outcomes was inconclusive. Most studies demonstrated a low risk of bias. CONCLUSIONS: TDM-guided piperacillin dosing in CRRT patients improved target attainment rates (≥80%). Mortality rates ranged from 17% to 56%, with inconsistent correlations between drug exposures and survival. Supratherapeutic concentrations were linked to higher mortality. Standardized TDM protocols are needed. Future research should establish clear exposure-response relationships and the impact of TDM on clinical outcomes.

Improved HPLC method with automated pre-column sample derivatisation for serum pegylated L-asparaginase activity measurement in paediatric acute lymphoblastic leukaemia patients.

Therapeutic drug monitoring of pegylated L-asparaginase (ASNase) ensures the drug effectiveness in childhood acute lymphoblastic leukaemia (ALL) patients. The biological drug property with variable immunogenic host clearance, and the prescription of its generic formulation urge the need for a reliable assay to ensure an optimal treatment and improve outcome. This study aimed to optimise an existing isocratic reversed-phase high performance liquid chromatography (RP-HPLC) method with an automated pre-column sample derivatisation and injection program, and a computational algorithm for measuring serum pegylated ASNase activity in children with ALL. Nath et al.'s method in 2009 was adopted and modified using a pegylated ASNase. A set of Microsoft Excel macros was developed for the serum drug activity computation. An Agilent InfinityLab LC Series 1260 Infinity II Quaternary System with fluorescence detection was employed with an Agilent Poroshell 120 EC-C18 4.6×100 mm, 2.7 µm analytical column. System flow rate was optimised to 2.0 mL/min with 40×10-6/bar pump compressibility. The O-phthaldialdehyde (OPA) solution composition was optimised to 1 % o-phthaldialdehyde, 0.8 % 2-mercaptoethanol, 7.13 % methanol, and 1.81 % sodium tetraborate. The pre-column derivatisation program mixed 0.1 µL sample with 25 µL OPA solution before the automated injection. Method validation was according to the ICH guidelines. Total analysis time was 15 min, with L-aspartic acid eluted at 0.96 min and internal standard at 4.7 min. The calibration curves showed excellent linearity (R ≥0.9999). Interday precision for the drug activity at 0.1 IU/mL, 0.5 IU/mL, and 1 IU/mL were 4.15 %, 3.05 %, and 3.09 % (n = 6). Mean %error for the drug activity at 0.1 IU/mL, 0.5 IU/mL, and 1 IU/mL were 0.90±4.41 %, -1.37±3.04 %, and -3.03±3.02 % (n = 6). Limit of quantitation was 0.03 IU/mL. Majority of the patients' serum drug activity fell within the assay calibration range. Our improved method is automated, having shorter analysis time with a well-maintained separation resolution that enables a high-throughput analysis for application.

A Comparison of the Incidence Rate for Joint Bleeding and FVIII Consumption between On-Demand versus Prophylaxis Factor VIII Replacement Therapy and the Direct Cost of Prophylaxis Treatment in Severe Haemophilia A Patients.

Background: Haemophilia A is a bleeding disorder caused by inadequate clotting factor VIII (FVIII). There are two main modes of treatment approach in severe haemophilia A patients either with on-demand or prophylaxis therapy with clotting factor FVIII concentrates. In this study, a comparison was made between the bleeding incidence rate of the on-demand and prophylaxis group in severe haemophilia A patients at Ampang Hospital, Malaysia. Methods: A retrospective study involving patients with severe haemophilia was conducted. The patient's self-reported bleeding frequency was retrieved from the patient's treatment folder from January to December 2019. Results: Fourteen patients received on-demand therapy, while the other 24 patients received prophylaxis treatment. The total number of joint bleeds in the prophylaxis group was significantly lower compared to the on-demand group (2.79 bleeds versus 21.36 bleeds [P < 0.001]). Furthermore, the total annual usage of FVIII was higher in the prophylaxis group compared to the on-demand group (1,506 IU/kg/year [± 905.98] versus 365.26 IU/kg/year [± 223.90], P = 0.001). Conclusion: Prophylaxis FVIII therapy is an effective treatment in reducing the frequency of bleeding joints. However, this treatment approach is associated with high cost due to the high consumption of FVIII.

Mortality outcomes and predictors of failed thrombolysis following STEMI thrombolysis in a non-PCI capable tertiary hospital: a 5-year analysis.

Pharmacological reperfusion remains the primary strategy for ST-elevation myocardial infarction (STEMI) in low- and medium-income countries. Literature has reported inconsistent incidences and outcomes of failed thrombolysis (FT). This study aimed to identify the incidence, mortality outcomes and predictors of FT in STEMI pharmacological reperfusion. This single-centre retrospective cohort study analyzed data on consecutive STEMI patients who received thrombolytic therapy from 2016 to 2020 in a public tertiary hospital. Total population sampling was used in this study. Logistic regression analyses were used to assess independent predictors of the mortality outcomes and FT. We analyzed 941 patients with a mean age of 53.0 ± 12.2 years who were predominantly male (n = 846, 89.9%). The in-hospital mortality was 10.3% (n = 97). FT occurred in 86 (9.1%) patients and was one of the predictors of mortality (aOR 3.847, p < 0.001). Overall, tenecteplase use (aOR 1.749, p = 0.021), pre-existing hypertension (aOR 1.730, p = 0.024), history of stroke (aOR 4.176, p = 0.004), and heart rate ≥ 100 bpm at presentation (aOR 2.333, p < 0.001) were the general predictors of FT. The predictors of FT with streptokinase were Killip class ≥ II (aOR 3.197, p = 0.004) and heart rate ≥ 100 bpm at presentation (aOR 3.536, p = 0.001). History of stroke (aOR 6.144, p = 0.004) and heart rate ≥ 100 bpm at presentation (aOR 2.216, p = 0.015) were the predictors of FT in STEMI patients who received tenecteplase. Mortality following STEMI thrombolysis remained high in our population and was attributed to FT. Identified predictors of FT enable early risk stratification to evaluate the patients' prognosis to manage them better.

Vitamin D insufficiency is high in Malaysia: A systematic review and meta-analysis of studies on vitamin D status in Malaysia.

Purpose: To estimate the vitamin D status of participants residing in Malaysia. Methods: PubMed, Scopus, Web of Science, and MyJurnal were searched up to June 2022 without language restrictions. Studies that reported the 25-hydroxyvitamin D [25(OH)D] concentrations and defined their cut-off for deficiency or insufficiency from healthy participants residing in Malaysia were included. The random effects model was used to pool vitamin D status using established cut-offs of <30, <50, and <75 nmol/L according to age group. Results: From 299 studies screened, 32 studies were included in the meta-analysis. The pooled proportion for <30 nmol/L was 21% (95% CI 9-36, n = 2,438 from 10 studies), while the pooled proportion <50 nmol/L was 64% (95% CI 56-72, n = 13,977 from 30 studies), and <75 nmol/L was 85% (95% CI 61-100, n = 1,376 from five studies). Heterogeneity was high (I2 ranged from 98-99%). Higher proportions of vitamin D insufficiency (defined as <50 nmol/L) were found in participants living in the urban areas (compared to rural areas), in females (compared to males), and in Malays and Malaysian Indians (compared to Malaysian Chinese) ethnicities. Conclusion: More than half of Malaysians have insufficient vitamin D levels, despite being a country that is close to the equator. We strongly urge prompt public health measures to improve the vitamin D status in Malaysia. Systematic review registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021260259].

Impact of COVID-19 pandemic on STEMI thrombolysis and Emergency Department's performance in a non-PCI capable tertiary hospital.

INTRODUCTION: Some guidelines had recommended "thrombolysis first" in ST-elevated myocardial infarction (STEMI) during the Coronavirus Disease 2019 (COVID-19) outbreak. The impact of COVID-19 solely on STEMI thrombolysis is lacking as most studies reported outcomes related to percutaneous coronary intervention (PCI) setting. Thus, this study aimed to assess the impact of the COVID-19 pandemic on STEMI thrombolysis outcomes and the Emergency Department's performance in a non-PCI capable centre. METHODS: This single-centre retrospective study analysed data on consecutive STEMI patients who received thrombolytic therapy from May 2019 to December 2020 (20 months) in a non-PCI capable tertiary hospital. Total population sampling was used in this study. We compared all patients' characteristics and outcomes ten months before and during the pandemic. Regression models were used to assess the impact of COVID-19 pandemic on door-to-needle time (DNT), mortality, bleeding events, and the number of overnight stays. RESULTS AND DISCUSSION: We analysed 323 patients with a mean age of 52.9 ± 12.9 years and were predominantly male (n = 280, 88.9%). There was a 12.5% reduction in thrombolysis performed during the pandemic. No significant difference in timing from symptoms onset to thrombolysis and DNT was observed. In-hospital mortality was significantly higher during the pandemic (OR 2.02, 95% CI 1.02-4.00, p = 0.044). Bleeding events post thrombolysis remained stable and there was no significant difference in the number of overnight stays during the pandemic. CONCLUSION: STEMI thrombolysis cases were reduced during the COVID-19 pandemic, with an inverse increase in mortality despite the preserved Emergency Department performance in timely thrombolysis.

Use of Complementary and Alternative Medicine and Adherence to Medication Therapy Among Stroke Patients: A Meta-analysis and Systematic Review.

Purpose: To identify the use patterns of complementary and alternative medicine (CAM) and its impact on medication adherence among patients with stroke. Method: A systematic search through Science Direct, Google Scholar, and PubMed was performed to identify potential studies up to June 2021.The primary outcome was CAM use, and the secondary outcome was medication adherence among patients with stroke. Articles included in the review met the following criteria: 1) patients with stroke ≥18 years old on prescribed medications, and 2) medication adherence reported status. Meta-analyses were conducted to estimate the pooled prevalence of complementary and alternative medicine and adherence in stroke patients using a random-effects model. Results: A total of 1,330 studies were screened, of which 22 were included in the final analysis. The type of studies included were cross-sectional surveys, cohort studies, retrospective studies and prospective survey. The pooled prevalence of CAM usage was at 38% (29-48% CI) and medication non-adherence among stroke patients was at 29% (20-48% CI). The most common reason for inadequate stroke therapy and higher dependence on CAM was the patients' lack of knowledge and the regimen complexity of the medication. Other factors for medication non-adherence were forgetfulness, side effects, cost, and lack of doctor-patient communication. Conclusion: A low prevalence of CAM usage and non-adherence to medications was observed among patients with stroke. Studies investigating the association between CAM usage and medication adherence among patients with stroke are scarce and future researches are needed to explore the influence of CAM use on stroke medication adherence.

A systematic review and meta-analysis of dabigatran peak and trough concentration in adults.

Dabigatran etexilate is an oral direct thrombin inhibitor used in preventing thromboembolism in patients with atrial fibrillation and several other conditions. Routine dabigatran concentration monitoring is not recommended in clinical practice; however, measurement of dabigatran concentration may be required in several conditions. This study aims to pool the peak and trough dabigatran concentration from real-world studies. A systematic review was performed to identify studies that measured the peak and trough dabigatran concentrations. Observational studies reporting dabigatran peak or trough concentrations and patients' clinical characteristics of either sex, age or weight were included. Random-effect meta-analyses and metaregression were conducted to pool dabigatran concentrations and to identify the correlation between factors affecting dabigatran concentrations. Fifteen studies with a total of 1226 patients were included. The pooled peak dabigatran concentration was 133 ng/mL (95% CI: 113-154, I2  = 86%, n = 655), while the pooled dabigatran trough concentration was 80 ng/mL (95% CI: 69-91, I2  = 93%, n = 1010). Metaregression analyses suggested that age is significantly correlated to trough concentration, while body weight and creatinine clearance significantly correlated to peak concentration. Subgroup results revealed that dabigatran concentration when measured with liquid chromatography-tandem mass spectrometry was higher than haemoclot thrombin inhibitor assay. Several guidelines have proposed dabigatran concentrations target range and the pooled dabigatran concentrations were in line with the suggested range. Further studies to correlate dabigatran concentrations and clinical outcomes is warranted to improve the safety and efficacy monitoring of dabigatran therapy.

Prescribing Practices of Intravenous Immunoglobulin in Tertiary Care Hospitals in Malaysia: A Need for a National Guideline for Immunoglobulin Use.

Rational use of drug involves the use of medicine as per clinical guidelines. Given the steady increase in the clinical utility of intravenous immunoglobulin (IVIG) either as licensed or off-label use, concerns are being raised about the possibility of supply shortages that could significantly impact patient care. Therefore, there is a need to regulate and to promote the rational use of this valuable medication. This cross-sectional chart review study attempts to evaluate the prescribing patterns of IVIG at two tertiary hospitals in Malaysia. Patients' medical files and dispensing records were examined and compared with current guidelines. A total of 348 prescriptions for IVIG were written during the 1-year study period. The highest usage of IVIG was for neurological (47.9%), immunological (27.5%), and hematological conditions (20%). The number of prescriptions with the US Food and Drug Administration (FDA) licensed indications and off-label indications was 148 (42.5%) and 200 (57.5%), respectively. Age (OR: 1.02, 95% CI: 1.01-1.03, p = 0.003) and those admitted to the critical care units (OR: 11.11, 95% CI: 5.60-22.05, p < 0.001) were significant factors for receiving IVIG for an off-label indication. Most prescriptions (79%) had appropriate dosing. Significant factors associated with receiving inappropriate dose of IVIG include age (OR: 0.93, 95% CI: 0.89-0.97, p = 0.001) and those admitted to the critical care units (OR: 10.15, 95% CI: 3.81-27.06, p < 0.001). This study advocates the development and implementation of evidence-based clinical guidelines with prioritization protocol to ensure rational use of IVIG.

Revisiting miRNA-21 as a Therapeutic Strategy for Myocardial Infarction: A Systematic Review.

ABSTRACT: Several types of cardiovascular cells use microRNA-21 ( miR-21 ), which has been linked to cardioprotection. In this study, we systematically reviewed the results of published papers on the therapeutic effect of miR-21 for myocardial infarction. Studies described the cardioprotective effects of miR-21 to reduce infarct size by improving angiogenesis, antiapoptotic, and anti-inflammatory mechanisms. Results suggest that cardioprotective effects of miR-21 may work synergistically to prevent the deterioration of cardiac function during postischemia. However, there are other results that indicate that miR-21 positively regulates tissue fibrosis, potentially worsening a postischemic injury. The dual functionalities of miR-21 occur through the targeting of genes and signaling pathways, such as PTEN , PDCD4 , KBTBD7 , NOS3 , STRN , and Spry-1 . This review provides insights into the future advancement of safe miR-21 -based genetic therapy in the treatment of myocardial infarction.

Bleeding and Thromboembolic Events in Patients with Non-Valvular Atrial Fibrillation Treated with Apixaban or Rivaroxaban.

Rivaroxaban and apixaban are effective oral anticoagulants, but their usage has been associated with an increased risk of bleeding events. This study examined the bleeding and thromboembolic events of rivaroxaban and apixaban. Medical records from 114 patients (rivaroxaban n = 64, apixaban n = 80) treated for stroke prevention in atrial fibrillation at a tertiary hospital in Malaysia were retrospectively reviewed. Patients with bleeding or stroke/systemic embolism events were identified and the bleeding risk factors were investigated using logistic regression analysis. Stroke or systemic embolism after treatment with Factor Xa (FXa) inhibitor occurred in 12 (8.33%) of the patients, 5 (3.47%) were ischaemic stroke and 7 (4.86%) of them were presented with myocardial infarction. Bleeding occurred in 32 (22.20%) patients, where 7 (4.90%) were presented with major bleeding (rivaroxaban n = 3, apixaban n = 4), while another 25 (17.40%) experienced clinically relevant non-major bleeding. Furthermore, concomitant antiplatelet used and serum creatinine level were significant predictors of bleeding events (P < 0.05). In conclusion, stroke or systemic embolism events were low for both drugs, but this may be an underestimate of the true prevalence due to the small sample size in the present study.

Clinical profile and predictors of 30-day all-cause mortality of ST-elevation myocardial infarction (STEMI) patients receiving fibrinolytic therapy in an Asian population.

BACKGROUND: Fibrinolysis remains the primary reperfusion strategy for ST-elevation myocardial infarction (STEMI) in many Asian countries. The outcomes and factors affecting mortality in STEMI fibrinolysis in the Asian population are lacking despite being widely used. OBJECTIVES: This study aimed to assess the clinical profile of patients and predictors affecting STEMI mortality in an Asian population. METHODS: This single-center retrospective study analyzed data from STEMI patients who received fibrinolytic therapy from 2016 to 2020 in a tertiary hospital. Logistic regression analysis was performed to identify the significant predictors of the 30-day all-cause mortality, the primary outcome. RESULTS: A total of 859 patients were included. Their mean age was 53.6 ±12.1 years and they were predominantly male (n=769, 89.4%). The majority of them had anterior involvement STEMI (n = 477, 55.5%) and presented with Killip ≥ II (n = 424, 49.4%). The 30-day all-cause mortality was 12.0% (n =  103). The final model found six predictors for 30-day mortality: age ≥75 (aOR 4.784, p < 0.001), female gender (aOR 2.869, p = 0.001), pre-existing hypertension (aOR 1.623, p = 0.046), anterior myocardial infarction (MI) (aOR 1.947, p < 0.001), Killip class (p < 0.001) and heart rate ≥100 at presentation (aOR 1.823, p =  0.016). Following fibrinolytic therapy, five predictors were found to affect 30-day mortality, i.e. failed fibrinolysis (aOR 2.094, p = 0.041), bleeding events, congestive heart failure (aOR 3.554, p = 0.046), ventricular fibrillation/ tachycardia (aOR 5.920, p < 0.001), and atrial fibrillation/ flutter (aOR 2.968, p = 0.016). CONCLUSION: Our STEMI patients were younger and more ill at presentation. The risk predictors on 30-day all-cause mortality identified in our Asian population allow the clinicians to better triage and manage STEMI patients.

Adverse Drug Reactions of Antihypertensives and CYP3A5*3 Polymorphism Among Chronic Kidney Disease Patients.

Chronic kidney disease (CKD) patients may be more susceptible to adverse drug reactions (ADRs), given their complex medication regimen and altered physiological state driven by a decline in kidney function. This study aimed to describe the relationship between CYP3A5*3 polymorphism and the ADR of antihypertensive drugs in CKD patients. This retrospective, multi-center, observational cohort study was performed among adult CKD patients with a follow-up period of up to 3 years. ADRs were detected through medical records. CYP3A5*3 genotyping was performed using the direct sequencing method. From the 200 patients recruited in this study, 33 (16.5%) were found to have ADRs related to antihypertensive drugs, with 40 ADRs reported. The most frequent ADR recorded was hyperkalemia (n = 8, 20.0%), followed by bradycardia, hypotension, and dizziness, with 6 cases (15.0%) each. The most common suspected agents were angiotensin II receptor blockers (n = 11, 27.5%), followed by angiotensin-converting enzyme inhibitors (n = 9, 22.5%). The CYP3A5*3 polymorphism was not found to be associated with antihypertensive-related ADR across the genetic models tested, despite adjustment for other possible factors through multiple logistic regression (p > 0.05). After adjusting for possible confounding factors, the factors associated with antihypertensive-related ADR were anemia (adjusted odds ratio [aOR] 5.438, 95% confidence interval [CI]: 2.002, 14.288) and poor medication adherence (aOR 3.512, 95% CI: 1.470, 8.388). In conclusion, the CYP3A5*3 polymorphism was not found to be associated with ADRs related to antihypertensives in CKD patients, which requires further verification by larger studies.

The outcomes of reperfusion therapy with streptokinase versus tenecteplase in ST-elevation myocardial infarction (STEMI): a propensity-matched retrospective analysis in an Asian population.

Background Fibrinolysis using streptokinase or tenecteplase remains the primary reperfusion strategy for ST-elevation myocardial infarction (STEMI) in many Asian countries, including Malaysia. Comparative outcomes of these two fibrinolytic agents in the Asian population were inconclusive despite being widely used. Aim We aimed to assess and compare the outcomes of streptokinase versus tenecteplase in STEMI reperfusion of an Asian population. Method This single-centre retrospective study analysed data on STEMI patients who received fibrinolytic therapy from 2016 to 2020 in the Emergency Department of the largest tertiary hospital in Malaysia. Total population sampling was used in this study. Based on the propensity score matching, 359 patients receiving streptokinase were matched against 359 patients receiving tenecteplase by incorporating 16 variables that potentially affect mortality. 30-day mortality, stroke and major bleeding were the primary outcome measures. Results There was no significant difference in 30-day mortality between streptokinase (n = 39, 11.2%) and tenecteplase (n = 46, 13.2%) groups (p = 0.418). The rates of ischemic strokes [streptokinase (n = 1, 0.3%) versus tenecteplase (n = 3, 0.9%), p = 0.624], intracranial haemorrhage [streptokinase (n = 3, 0.9%) versus tenecteplase (n = 1, 0.3%), p = 0.624] and major bleeding [streptokinase (n = 4, 1.1%) versus tenecteplase (n = 3, 0.9%), p = 0.624], were comparable for the two groups. The incidences of failed thrombolysis were significantly higher in the tenecteplase arm. Hypotension and allergic reaction were significantly higher in the streptokinase arm. Conclusion Streptokinase and tenecteplase are fibrinolytic agents with similar efficacy and safety in STEMI reperfusion therapy in our Asian population.

A systematic review of population pharmacokinetic analyses of polyclonal immunoglobulin G therapy.

BACKGROUND: Population pharmacokinetics (popPK) using the nonlinear mixed-effect (NLME) modeling approach is an essential tool for guiding dose individualization. Several popPK analyses using the NLME have been conducted to characterize the pharmacokinetics of immunoglobulin G (IgG). OBJECTIVE: To summarize the current information on popPK of polyclonal IgG therapy. METHOD: A systematic search was conducted in the PubMed and Web of Science databases from inception to December 2020. Additional relevant studies were also included by reviewing the reference list of the reviewed articles. All popPK studies that employed the NLME modeling approach were included and data were synthesized descriptively. RESULTS: This review included seven studies. Most of the popPK models were developed in patients with primary immunodeficiency (PID). IgG pharmacokinetics was described as a two-compartment model in five studies, while it was described as a one-compartment model in two other studies. Among all tested covariates, weight was consistently identified as a significant predictor for clearance (CL) of IgG. Whereas, weight and disease type were found to be significant predictors for the volume of distribution in central compartment (Vc). In a typical 70 kg adult, the median estimated values of Vc and CL were 4.04 L and 0.144 L/day, respectively. The between subject variability of Vc was considered large. Only two studies evaluated their models using external data. CONCLUSIONS: Seven popPK studies of IgG were found and discussed, with only weight being a significant covariate across all studies. Future studies linking pharmacokinetics with pharmacodynamics in PID and other patient populations are required.

Effects of CYP3A5 Polymorphism on Rapid Progression of Chronic Kidney Disease: A Prospective, Multicentre Study.

Personalised medicine is potentially useful to delay the progression of chronic kidney disease (CKD). The aim of this study was to determine the effects of CYP3A5 polymorphism in rapid CKD progression. This multicentre, observational, prospective cohort study was performed among adult CKD patients (≥18 years) with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, who had ≥4 outpatient, non-emergency eGFR values during the three-year study period. The blood samples collected were analysed for CYP3A5*3 polymorphism. Rapid CKD progression was defined as eGFR decline of >5 mL/min/1.73 m2/year. Multiple logistic regression was then performed to identify the factors associated with rapid CKD progression. A total of 124 subjects consented to participate. The distribution of the genotypes adhered to the Hardy-Weinberg equilibrium (X2 = 0.237, p = 0.626). After adjusting for potential confounding factors via multiple logistic regression, the factors associated with rapid CKD progression were CYP3A5*3/*3 polymorphism (adjusted Odds Ratio [aOR] 4.190, 95% confidence interval [CI]: 1.268, 13.852), adjustments to antihypertensives, young age, dyslipidaemia, smoking and use of traditional/complementary medicine. CKD patients should be monitored closely for possible factors associated with rapid CKD progression to optimise clinical outcomes. The CYP3A5*3/*3 genotype could potentially be screened among CKD patients to offer more individualised management among these patients.

Population pharmacokinetic modelling of intravenous immunoglobulin in patients with predominantly antibody deficiencies.

AIMS: There is considerable interpatient variability in the pharmacokinetics (PK) of intravenous immunoglobulin G (IVIG), causing difficulty in optimizing individual dosage regimen. This study aims to estimate the population PK parameters of IVIG and to investigate the impact of genetic polymorphism of the FcRn gene and clinical variability on the PK of IVIG in patients with predominantly antibody deficiencies. METHODS: Patients were recruited from four hospitals. Clinical data were recorded and blood samples were taken for PK and genetic studies. Population PK parameters were estimated by nonlinear mixed-effects modelling in Monolix®. Models were evaluated using the difference in objective function value, goodness-of-fit plots, visual predictive check and bootstrap analysis. Monte Carlo simulation was conducted to evaluate different dosing regimens for IVIG. RESULTS: A total of 30 blood samples were analysed from 10 patients. The immunoglobulin G concentration data were best described by a one-compartment model with linear elimination. The final model included both volume of distribution (Vd) and clearance (CL) based on patient's individual weight. Goodness-of-fit plots indicated that the model fit the data adequately, with minor model mis-specification. Genetic polymorphism of the FcRn gene and the presence of bronchiectasis did not affect the PK of IVIG. Simulation showed that 3-4-weekly dosing intervals were sufficient to maintain IgG levels of 5 g L-1 , with more frequent intervals needed to achieve higher trough levels. CONCLUSIONS: Body weight significantly affects the PK parameters of IVIG. Genetic and other clinical factors investigated did not affect the disposition of IVIG.

Antioxidant and Anti-Inflammatory Effects of Genus Gynura: A Systematic Review.

Background: Gynura species have been used traditionally to treat various ailments, such as fever, pain, and to control blood glucose level. This systematic review critically discusses studies regarding Gynura species that exhibited antioxidant and anti-inflammatory effects, thus providing perspectives and instructions for future research of the plants as a potential source of new dietary supplements or medicinal agents. Methods: A literature search from internet databases of PubMed, Scopus, Science Direct, e-theses Online Service, and ProQuest was carried out using a combination of keywords such as "Gynura," "antioxidant," "anti-inflammatory," or other related words. Research articles were included in this study if they were experimental (in vitro and in vivo) or clinical studies on the antioxidant or anti-inflammatory effects of Gynura species and if they were articles published in English. Results: Altogether, 27 studies on antioxidant and anti-inflammatory effects of Gynura species were selected. The antioxidant effects of Gynura species were manifested by inhibition of reactive oxygen species production and lipid peroxidation, modulation of glutathione-related parameters, and enzymatic antioxidant production or activities. The anti-inflammatory effects of Gynura species were through the modulation of inflammatory cytokine production, inhibition of prostaglandin E2 and nitric oxide production, cellular inflammatory-related parameters, and inflammation in animal models. The potential anti-inflammatory signaling pathways modulated by Gynura species are glycogen synthase kinase-3, nuclear factor erythroid 2-related factor 2, PPARγ, MAPK, NF-κB, and PI3K/Akt. However, most reports on antioxidant and anti-inflammatory effects of the plants were on crude extracts, and the chemical constituents contributing to bioactivities were not clearly understood. There is a variation in quality of studies in terms of design, conduct, and interpretation, and in-depth studies on the underlying mechanisms involved in antioxidant and anti-inflammatory effects of the plants are in demand. Moreover, there is limited clinical study on antioxidant and anti-inflammatory effects of Gynura species. Conclusion: This review highlighted antioxidant and anti-inflammatory effects of genus Gynura and supported their traditional uses to treat oxidative stress and inflammatory-related diseases. This review is expected to catalyze further studies on genus Gynura. However, extensive preclinical data need to be generated from toxicity and pharmacokinetic studies before clinical studies can be pursued for their development into clinical medicines to treat oxidative stress and inflammatory conditions.