Variability in the pharmacokinetics of mycophenolic acid: Implications for therapeutic drug monitoring

Mycophenolate mofetil (MMF) is an immunosuppressive drug used to prevent rejection following solid organ transplantation. MMF was introduced in 1995 with a recommended fixed-dose regimen of 1 g twice daily. Nowadays, dose individualization using therapeutic drug monitoring (TDM) of the area under the concentration-time curve from 0 to 12 hours postdose (AUC0-12) of the active compound, mycophenolic acid (MPA), is advocated to optimize the treatment. The recommended target range for the MPA AUC0-12 in renal transplant recipients is 30-60 mg*h/L. A practical and suitable manner of determining the MPA AUC0-12 are abbreviated AUC measurements, in which the AUC0-12 is estimated by a limited sampling strategy. In renal transplant recipients, it has been shown that limited sampling strategies estimate MPA AUC0-12 with sufficient accuracy and precision. The aim of this thesis was to further explain the differences in the pharmacokinetics of MMF seen between renal transplant recipients, investigate the validity of these results in other populations, or when different formulations are used, and to describe the effects of these results on individualization of the MMF treatment. In Chapter 1 of this thesis, an overview of the pharmacokinetics of MPA in renal transplant recipients and the added value of TDM are discussed. MPA is a highly protein bounded drug, which binds reversibly to albumin. The free fraction is thought to be responsible for the immunosuppressive effect of MPA. Cyclosporine comedication, low plasma albumin level, and impaired renal function are associated with a decrease in total MPA AUC, but the unbound concentration is hardly affected. The effect of these covariates on total and unbound MPA concentrations is clarified in Chapter 2.1. The effect of MMF dose on the pharmacokinetics of MPA is evaluated in Chapter 2.2. In Chapter 2.3 the differences in the pharmacokinetics of MPA between adult and pediatric renal transplant recipients are examined. Besides solid organ transplantation, MMF is increasingly used to prevent graft-versu

Clinical applications of population pharmacokinetic models of antibiotics: Challenges and perspectives

Because of increasing antimicrobial resistance and the shortage of new antibiotics, there is a growing need to optimize the use of old and new antibiotics. Modelling of the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of antibiotics can support the optimization of dosing regimens. Antimicrobial efficacy is determined by susceptibility of the drug to the microorganism and exposure to the drug, which relies on the PK and the dose. Population PK models describe relationships between patients characteristics and drug exposure. This article highlights three clinical applications of these models applied to antibiotics: 1) dosing evaluation of old antibiotics, 2) setting clinical breakpoints and 3) dosing individualization using therapeutic drug monitoring (TDM). For each clinical application, challenges regarding interpretation are discussed. An important challenge is to improve the understanding of the interpretation of modelling results for good implementation of the dosing recommendations, clinical breakpoints and TDM advices. Therefore, also background information on PK/PD principles and approaches to analyse PK/PD data are provided

Personalized immunosuppression in elderly renal transplant recipients

The number of elderly people has increased considerably over the last decades, due to a rising life expectancy and ageing populations. As a result, an increased number of elderly with end-stage-renal-disease are diagnosed, for which the preferred treatment is renal transplantation. Over the past years the awareness of the elderly as a specific patient population has grown, which increases the importance of research in this group.Elderly patients often receive kidneys from elderly donors while younger donor kidneys are preferentially reserved for younger recipients. Although the rate of acute rejection after transplantation is lower in the elderly, these rejections may lead to graft loss more frequently, as kidneys from elderly donors have marginal reserve capacity. To prevent acute rejection, immunosuppressive therapy is needed. On the other hand, elderly patients have a higher risk to die from infectious complications, and thus less immunosuppression would be preferable.Immunosuppressive treatm

Best practices, implementation and challenges of outpatient parenteral antimicrobial therapy:results of a worldwide survey among healthcare providers.

Background: Outpatient Parenteral Antimicrobial Therapy (OPAT) is considered a patient-friendly and cost-effective practice. Patients in the OPAT service can be at risk for developing adverse events. Due to extensive variations in practice, guidelines have been developed to minimize the risks. Objectives: In this first worldwide survey on OPAT, we explored the current OPAT services around the world, adherence to recommendations and identified best practices and challenges from different perspectives. Methods: An e-survey was conducted and consisted of questions about demographics, characteristics of the OPAT service, role of pharmacy, future developments, and respondents’ views on improvements as well as best practices. Results: A total of 126 responses from 28 countries were included. Seventy-eight percent (78%) of the respondents stated that their facility provides antimicrobial therapy in the outpatient setting, whereas 22% did not. Forty-two percent (42%) of the hospitals with OPAT services had a specialized OPAT service, while 14% lacked specialized services and 22% had a partially specialized team in place. In facilities with a specialized OPAT service, the number of mandatory infectious disease (ID) consultations before discharge and clinical monitoring by an ID specialist or OPAT team member, the frequency of monitoring, and the availability of an OPAT registry were higher. A multidisciplinary team’s presence was commonly noted as best practices. On the other hand, respondents experienced difficulties with reimbursement and lack of standardization in the screening, follow-up and monitoring of patients. Conclusion: This survey provides a better understanding of the implementation and practices of OPAT services globally and describes best practices and the challenges from different professionals.</p

Dried blood spot analysis for the quantification of vancomycin and creatinine using liquid chromatography – tandem mass spectrometry:Method development and validation

Background: Vancomycin is a widely used antibiotic for the treatment of gram-positive bacterial infections, especially for methicillin-resistant Staphylococcus aureus (MRSA) infections. Due to a small therapeutic range and large inter-patient variability, therapeutic drug monitoring (TDM) of vancomycin is required to minimize toxicity and maximize treatment efficacy. Venous blood sampling is mostly applied for TDM of vancomycin, although this widely used sampling method is more invasive compared to less painful alternatives, such as the dried blood spot (DBS) method, which can be performed at home. Method: We developed an UPLC-MS/MS method for the quantification of vancomycin and creatinine in DBS. A fast sample preparation and short analysis run time of 5.2 min were applied, which makes this method highly suitable for clinical settings. Validation was performed according to international (FDA and EMA) guidelines. Results: The validated concentration range was found linear for creatinine from 41.8 µmol/L to 722 µmol/L and for vancomycin from 3.8 mg/L to 76.6 mg/L (r2 &gt; 0.990) and the inaccuracies, imprecisions, hematocrit effects, and recoveries were &lt; 15 % for both compounds. No significant carryover effect was observed. Conclusion: Hence, we successfully validated a quantification method for the simultaneous determination of creatinine and vancomycin in DBS.</p

Individualized dosing algorithms for tacrolimus in kidney transplant recipients:current status and unmet needs

Introduction: Tacrolimus is a potent immunosuppressive drug with many side effects including nephrotoxicity and post-transplant diabetes mellitus. To limit its toxicity, therapeutic drug monitoring (TDM) is performed. However, tacrolimus’ pharmacokinetics are highly variable within and between individuals, which complicates their clinical management. Despite TDM, many kidney transplant recipients will experience under- or overexposure to tacrolimus. Therefore, dosing algorithms have been developed to limit the time a patient is exposed to off-target concentrations. Areas Covered: Tacrolimus starting dose algorithms and models for follow-up doses developed and/or tested since 2015, encompassing both adult and pediatric populations. Literature was searched in different databases, i.e. Embase, PubMed, Web of Science, Cochrane Register, and Google Scholar, from inception to February 2023 Expert Opinion: Many algorithms have been developed, but few have been prospectively evaluated. These performed better than bodyweight-based starting doses, regarding the time a patient is exposed to off-target tacrolimus concentrations. No benefit in reduced tacrolimus toxicity has yet been observed. Most algorithms were developed from small datasets, contained only a few tacrolimus concentrations per person, and were not externally validated. Moreover, other matrices should be considered which might better correlate with tacrolimus toxicity than the whole-blood concentration, e.g. unbound plasma or intra-lymphocytic tacrolimus concentrations.</p

Variabiliteit in farmacokinetiek van intraveneuze paracetamol bij gezonde ouderen

BACKGROUND and OBJECTIVE: Paracetamol is the most used analgesic in older people. The physiological changes occurring with ageing influence the pharmacokinetics of paracetamol and its variability. A population pharmacokinetic analysis to describe the pharmacokinetics of intravenous paracetamol in fit older people was performed. Thereafter, simulations were conducted to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg q6h, q8h) using steady-state concentration (Cssmean) of 10 mg/L as target for effective analgesia. DESIGN and METHODS: A population pharmacokinetic-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit older people (median age = 77.3 years [61.8- 88.5], body weight = 79 kg [60-107]). All had received an intravenous paracetamol dose of 1000 mg – over 15 min – after elective knee surgery. RESULTS: A two-compartment pharmacokinetic-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css-mean of 9.2 mg/L (q6h) and 7.2 mg/L (q8h). Variability in paracetamol pharmacokinetics resulted in a Css-mean above 5.4 (q6h) and 4.1 mg/L (q8h) in 90%, and above 15.5 (q6h) and 11.7 mg/L (q8h) in 10% of the population. CONCLUSION: The target concentration was achieved in the average patient with 1000 mg q6h, while q8h resulted in underdosing for the majority of the population. Due to large unexplained interindividual variability in paracetamol pharmacokinetics a relevant proportion of the fit older people remained either under- or overexposed