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How accurate and precise are limited sampling strategies in estimating exposure to mycophenolic acid in people with autoimmune disease?

Abd Rahman AN, Tett SE, Staatz CE

Clin Pharmacokinet, 2014 Mar;53(3):227-245.
PMID: 24327238 DOI: 10.1007/s40262-013-0124-z

Mycophenolic acid (MPA) is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. Dosing to achieve a specific target MPA area under the concentration-time curve from 0 to 12 h post-dose (AUC12) is likely to lead to better treatment outcomes in patients with autoimmune disease than a standard fixed-dose strategy. This review summarizes the available published data around concentration monitoring strategies for MPA in patients with autoimmune disease and examines the accuracy and precision of methods reported to date using limited concentration-time points to estimate MPA AUC12. A total of 13 studies were identified that assessed the correlation between single time points and MPA AUC12 and/or examined the predictive performance of limited sampling strategies in estimating MPA AUC12. The majority of studies investigated mycophenolate mofetil (MMF) rather than the enteric-coated mycophenolate sodium (EC-MPS) formulation of MPA. Correlations between MPA trough concentrations and MPA AUC12 estimated by full concentration-time profiling ranged from 0.13 to 0.94 across ten studies, with the highest associations (r (2) = 0.90-0.94) observed in lupus nephritis patients. Correlations were generally higher in autoimmune disease patients compared with renal allograft recipients and higher after MMF compared with EC-MPS intake. Four studies investigated use of a limited sampling strategy to predict MPA AUC12 determined by full concentration-time profiling. Three studies used a limited sampling strategy consisting of a maximum combination of three sampling time points with the latest sample drawn 3-6 h after MMF intake, whereas the remaining study tested all combinations of sampling times. MPA AUC12 was best predicted when three samples were taken at pre-dose and at 1 and 3 h post-dose with a mean bias and imprecision of 0.8 and 22.6 % for multiple linear regression analysis and of -5.5 and 23.0 % for maximum a posteriori (MAP) Bayesian analysis. Although mean bias was less when data were analysed using multiple linear regression, MAP Bayesian analysis is preferable because of its flexibility with respect to sample timing. Estimation of MPA AUC12 following EC-MPS administration using a limited sampling strategy with samples drawn within 3 h post-dose resulted in biased and imprecise results, likely due to a longer time to reach a peak MPA concentration (t max) with this formulation and more variable pharmacokinetic profiles. Inclusion of later sampling time points that capture enterohepatic recirculation and t max improved the predictive performance of strategies to predict EC-MPS exposure. Given the considerable pharmacokinetic variability associated with mycophenolate therapy, limited sampling strategies may potentially help in individualizing patient dosing. However, a compromise needs to be made between the predictive performance of the strategy and its clinical feasibility. An opportunity exists to combine research efforts globally to create an open-source database for MPA (AUC, concentrations and outcomes) that can be used and prospectively evaluated for AUC target-controlled dosing of MPA in autoimmune diseases.
Fulltext Effects of recycling and bonding agent application on bond strength of stainless steel orthodontic brackets

Bahnasi FI, Abd-Rahman AN, Abu-Hassan MI

J Clin Exp Dent, 2013 Oct 1;5(4):e197-202.
PMID: 24455081 DOI: 10.4317/jced.51113

1) to assess different methods of recycling orthodontic brackets, 2) to evaluate Shear Bond Strength (SBS) of (a) new, (b) recycled and (c) repeated recycled stainless steel brackets (i) with and (ii) without bracket base primer.
Fulltext Exposure-effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis

Abd Rahman AN, Tett SE, Abdul Gafor HA, McWhinney BC, Staatz CE

Br J Clin Pharmacol, 2015 Nov;80(5):1064-75.
PMID: 25959850 DOI: 10.1111/bcp.12678

AIMS: The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis.
METHODS: Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C0 ), maximum concentration (Cmax ) and area under the concentration-time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events.
RESULTS: Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l(-1) h, P= 0.048) and Cmax (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l(-1) , P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l(-1) h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l(-1) h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l(-1) h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023).
CONCLUSIONS: This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis.
KEYWORDS: lupus nephritis; mycophenolic acid; pharmacodynamics; pharmacokinetics; prednisolone; treatment outcome
Study site: Nephrology and SLE Clinics, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia
Development of improved dosing regimens for mycophenolate mofetil based on population pharmacokinetic analyses in adults with lupus nephritis

Abd Rahman AN, Tett SE, Abdul Gafor HA, McWhinney BC, Staatz CE

Eur J Drug Metab Pharmacokinet, 2017 Dec;42(6):993-1004.
PMID: 28536776 DOI: 10.1007/s13318-017-0420-3

BACKGROUND AND OBJECTIVE: Mycophenolic acid (MPA) provides effective treatment for lupus nephritis patients. Owing to its large pharmacokinetic variability, it is questionable whether standard fixed dose therapy can achieve optimal MPA exposure. The aim of this study was to develop a population pharmacokinetic model of MPA and its metabolite, 7-O-MPA-β-glucuronide (MPAG), to identify important covariate influences and better predict patient dosing requirements.
METHODS: MPA and MPAG concentration-time profiles were collected from 25 patients receiving mycophenolate mofetil (MMF) with or without cyclosporine (CsA) co-therapy. Samples were collected pre-dose and at 1, 2, 4, 6 and 8 h post-dose on one or two occasions.
RESULTS: A total of 225 and 226 concentration-time measurements of MPA and MPAG, respectively, were used to develop the model, utilizing NONMEM® software. A two-compartment model with first-order absorption and elimination for MPA and a one-compartment model with first-order elimination and enterohepatic circulation (EHC) for MPAG best described the data. Apparent clearance of MPAG (CL/F MPAG) significantly decreased with reducing renal function and extent of EHC was reduced with concomitant CsA use. Simulations using the final model showed that a 70-kg subject with a creatinine clearance of 90 mL/min receiving concomitant CsA would require 1.25 g of MMF twice daily while a similar subject who did not receive concomitant CsA would require 0.75 g twice daily to achieve a MPA area under the concentration-time curve from 0 to 12 h (AUC0-12) of 45 mg·h/L.
CONCLUSION: A 'tiered' dosing approach considering patient renal function and CsA co-therapy, rather than a 'one dose fits all' approach, would help individualize MMF therapy in adult lupus nephritis patients to ensure more patients have optimal MPA exposure.
Study site: Nephrology and Systemic Lupus Erythematosus (SLE) Clinics, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia
Fulltext Liquid Chromatography Mass Spectrometry (LC-MS) analysis in determining the saliva protein of orthodontic patients during retention phase

Awang-Kechik NH, Ahmad R, Doustjalali SR, Sabet NS, Abd-Rahman AN

J Clin Exp Dent, 2019 Mar;11(3):e269-e274.
PMID: 31001398 DOI: 10.4317/jced.55546

Background: The biological responses involved during retention phase have been studied for many years but little is known about the effect of saliva proteome during retention phase of post-orthodontic treatment. This study aims to identify the protein profiles during retention phase in relation to biological processes involved by Liquid Chromatography Mass Spectrometry (LC-MS) approach.
Material and Methods: A total of 5 ml of unstimulated saliva was collected from each subject (10 non-orthodontic patients and 15 post-orthodontic patients with 6-months retention phase). Samples were then subjected to LC-MS analysis. The expressed proteins were identified and compared between groups. Incisor irregularity for both maxilla and mandible were determined with Little's Irregularity Index at 6-months retention phase.
Results: 146 proteins and 135 proteins were expressed in control and 6-months retention phase group respectively. 15 proteins were identified to be co-expressed between groups. Immune system process was only detected in 6-months retention phase group. Detected protein in immune system process was identified as Tyrosine-protein kinase Tec. Statistical significant of incisor irregularity was only found in mandible at 6-months retention phase.
Conclusions: Our study suggests that immune system process protein which is Tyrosine-protein kinase Tec could be used as biomarker for prediction of stability during retention phase of post-orthodontic treatment. Key words:Orthodontics, proteomics, retention, LC-MS, saliva.
Fulltext Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

Abdul-Aziz MH, Abd Rahman AN, Mat-Nor MB, Sulaiman H, Wallis SC, Lipman J, et al.

Antimicrob Agents Chemother, 2016 01;60(1):206-14.
PMID: 26482304 DOI: 10.1128/AAC.01543-15

Doripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood samples were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CL(CR)), such that a 30-ml/min increase in the estimated CL(CR) would increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CL(CR) of 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CL(CR) of >100 ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved.
Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis

Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, Rai V, Wong KK, Hasan MS, et al.

Intensive Care Med, 2016 Oct;42(10):1535-1545.
PMID: 26754759 DOI: 10.1007/s00134-015-4188-0

PURPOSE: This study aims to determine if continuous infusion (CI) is associated with better clinical and pharmacokinetic/pharmacodynamic (PK/PD) outcomes compared to intermittent bolus (IB) dosing in critically ill patients with severe sepsis.
METHODS: This was a two-centre randomised controlled trial of CI versus IB dosing of beta-lactam antibiotics, which enrolled critically ill participants with severe sepsis who were not on renal replacement therapy (RRT). The primary outcome was clinical cure at 14 days after antibiotic cessation. Secondary outcomes were PK/PD target attainment, ICU-free days and ventilator-free days at day 28 post-randomisation, 14- and 30-day survival, and time to white cell count normalisation.
RESULTS: A total of 140 participants were enrolled with 70 participants each allocated to CI and IB dosing. CI participants had higher clinical cure rates (56 versus 34 %, p = 0.011) and higher median ventilator-free days (22 versus 14 days, p MIC than the IB arm on day 1 (97 versus 70 %, p
Fulltext Knowledge, Perception, and Antibiotic Prescribing Practice in the Intensive Care Unit: Findings from the Malaysian Public Setting

Rozali MA, Abd Rahman NS, Sulaiman H, Abd Rahman AN, Atiya N, Wan Mat WR, et al.

J Pharm Bioallied Sci, 2020 Nov;12(Suppl 2):S804-S809.
PMID: 33828380 DOI: 10.4103/jpbs.JPBS_266_19

Introduction: Approach to managing infection in the intensive care unit (ICU) often varies between institutions and not many readily adapt to available local guidelines despite it was constructed to suite local clinical scenario. Malaysia already has two published guidelines on managing infection in the ICU but data on its compliance are largely unknown.
Objectives: A cross-sectional survey was carried out and sent to a total of 868 specialists working primarily in the ICU. The aim of this study was to explore knowledge, perception, and the antibiotic prescribing practice among specialists and advanced trainees in Malaysian ICU.
Materials and Methods: A cross-sectional survey was used, consisted of three sections: knowledge, perception, and antibiotic prescribing practice in ICU. Three case vignettes on hospital-acquired pneumonia (HAP), infected necrotizing pancreatitis (INP), and catheter-related bloodstream infection (CRBSI) were used to explore antibiotic prescribing practice.
Results: A total of 868 eligible subjects were approached with 104 responded to the survey. Three hundred eighty-nine antibiotics were chosen from seven different classes in the case vignettes. All respondents acknowledged the importance of pharmacokinetic/pharmacodynamic (PK/PD) in antibiotic optimization and majority (97.2%) perceived that current dosing is inadequate to achieve optimal PK/PD target in ICU patients. Majority (85.6%) believed that antibiotic dose should be streamlined to the organisms' minimum inhibitory concentration (MIC). In terms of knowledge, only 64.4% provided the correct correlations between antibiotics and their respective PK/PD targets. Compliance rates in terms of antibiotic choices were at 79.8%, 77.8%, and 27.9% for HAI, INP, and CRBSI, respectively.
Conclusion: Malaysian physicians are receptive to use PK/PD approach to optimize antibiotic dosing in ICU patients. Nonetheless, there are still gaps in the knowledge of antibiotic PK/PD as well as its application in the critically ill, especially for β-lactams.