Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases

ABSTRACT

Introduction: Biologic therapy has revolutionized the treatment of immune mediated inflammatory diseases (IMID), such as inflammatory bowel disease (IBD), rheumatoid and psoriatic arthritis, ankylosing spondylitis and psoriasis. Nevertheless, some patients exhibit primary nonresponse (PNR) or secondary loss of response (SLR) to biologics.

Areas covered: This collaborative review provides data on the role of therapeutic drug monitoring (TDM) in IMID for optimizing biologic therapy including infliximab, adalimumab, certolizumab pegol etanercept and golimumab vedolizumab, secukinumab and ustekinumab.

Expert opinion: Most exposure-response relationship studies show a positive correlation between biologic drug concentrations and favorable therapeutic outcomes in IMID with higher drug concentrations typically associated with more objective outcomes. Clinically, reactive TDM rationalizes the management of PNR and SLR to anti-tumor necrosis factor therapy and is emerging as the new standard of care in IBD as it is also more cost-effective than empiric dose escalation. Preliminary data suggest that proactive TDM with the goal to achieve a threshold drug concentration is associated with better therapeutic outcomes when compared to empiric drug optimization and/or reactive TDM of infliximab and adalimumab in IBD. However, more data from well-designed prospective studies are needed to prove the benefit of TDM-based algorithms in real life clinical practice in IMID.     

A Case of Septicaemic Melioidosis: Utility of Therapeutic Drug Monitoring and High-Dose Meropenem in Successful Management

Melioidosis is an emerging infectious disease of major public health importance. We describe a patient who presented with septicaemic melioidosis with multi-organ dysfunction. He had only marginal response on standard doses of meropenem. Therapeutic drug monitoring (TDM) revealed suboptimal concentration of meropenem following which drug dose was increased, with which he showed rapid clinical improvement and microbiological clearance. Melioidosis presents with multisystem involvement with disseminated abscess, standard dosing of meropenem may not be sufficient in achieving therapeutic levels and TDM with increased dosing in these critically ill patients will improve outcome.     

The Design and Implementation of A5146, a Prospective Trial Assessing the Utility of Therapeutic Drug Monitoring Using an Inhibitory Quotient in Antiretroviral-Experienced HIV-Infected Patients

Abstract

The AIDS Clinical Trials Group designed and implemented a prospective, randomized, strategy trial in antiretroviral-experienced, HIV-infected patients to evaluate the virologic impact of protease inhibitor dose escalation in response to therapeutic drug monitoring (TDM) with an inhibitory quotient, which integrates both drug exposure and viral drug resistance. In the process of developing this clinical trial, several unique challenges were identified that required innovative solutions. The major challenge was the need to integrate resistance testing, pharmacokinetic data, medication adherence, toxicity data, clinical assessments, randomization assignment, and protocol-specified clinical management in a way that could be utilized in real time by the protocol team, communicated promptly to the clinical sites, and transmitted accurately to the study database. In addition, the protocol team had to address the relative lack of commercially available TDM laboratories in the United States that were experienced in antiretroviral drug assays and a lack of familiarity with the principles of pharmacokinetic monitoring at participating clinical sites. This article outlines the rationale for the design of this strategy trial, specific barriers to implementation that were identified, and solutions that were developed with the hope that these experiences will facilitate the design and conduct of future trials of TDM.     

Flow cytometric monitoring of drug resistance in human tumor cells

Recent studies have identified a family of glycoproteins which moulate cellular transport of antibiotics, alkaloids and drugs used in cancer chemotherapy. By facilitating efflux of drugs from the intracellular domain, these proteins reduce cytotoxicity and thus confer drug resistance. With the availability of antibodies raised against these phenotypic markers of drug resistance, immunohistochemistry and flow cytometry has been used to study their distribution and expression in normal and tumor cells. As some of the drugs used in cancer chemotherapy and other dyes which are substrates for this efflux pump are fluorescent, laser flow cytometry can be used for rapid quantitation of cellular retention, efflux and heterogeneity in drug transport of a tumor cell population. This method can also be used to screen drugs which may block efflux of a chemotherpeutic drug and thus increase chemosensitivity of a drug resistant tumor. In the present report flow cytometric methods for the study of drug transport and its modulation in tumor cells are discussed.     

Therapeutic drug monitoring of imipenem and the incidence of toxicity and failure in hospitalized patients: a retrospective cohort study

Objectives

Therapeutic drug monitoring (TDM) of beta-lactam antibiotics is increasingly employed to ensure adequate antibiotic exposure and slow emergence of resistance. Imipenem's therapeutic range has not been defined; we report plasma concentrations and clinical outcomes of patients receiving imipenem for bacterial infections.

Cyclosporin drug monitoring: Comparison of four immunoassays and HPLC

Summary Cyclosporin blood trough levels were measured with four different immunoassays and high-performance liquid chromatography in 12 patients receiving low-dose steroids and CsA after kidney transplantation. These patients represent a selection with an uncomplicated posttransplant course and received no drugs with a known influence on CsA pharmacokinetics. The use of specific antibodies against the parent drug yielded levels comparable to those detected by HPLC. CsA levels measured with nonspecific antibodies exceeded those measured with specific ones by a factor of two to three. All immunoassay-detected CsA levels correlated significantly with the HPLC-determined CsA levels. In addition, blood levels of the CsA metabolites 1, 17, 18, and 21 were determined by HPLC. In one additional patient, who was under tuberculostatic treatment and had a transitory deterioration of liver function, levels of nonspecificantibody-determined CsA rose, as confirmed by rising levels of metabolite 17, while those of the parent drug fell. We conclude that routine drug monitoring should include at least one immunoassay with a specific antibody detecting the unchanged CsA, and a supplementary immunoassay with a nonspecific antibody detecting a composition of cross-reacting metabolites plus the unchanged substance. If available, HPLC should be used to confirm levels of CsA and its metabolites in patients with suspected alteration of their CsA metabolism.Abbreviations CsA cyclosporin - RIA radioimmunoassay - HPLC high-performance liquid chromatography - nAB nonspecific antibody - sAB specific antibody     

Compliance and adverse drug reactions: a prospective study with ethinylestradiol using continuous compliance monitoring

Summary This study examined the relationship between adverse reactions and patient compliance with ethinylestradiol at 40 g twice daily versus 20 g four times daily. In a randomized study 61 female patients with primary- infertility were prescribed the drug twice daily (n = 31) or four times daily (n = 30). Ethinylestradiol was administered for 7 days before the sperm cervical mucus penetration-test was performed for hormonal standardization of the cervical mucus quality. Drug compliance was measured by continuous monitoring using the Medication Event Monitoring System. Two parameters were evaluated: percentage of prescribed doses taken (administration compliance) and adherence to the prescribed dose schedule (regimen compliance, number of days with two or four dosing events recorded). Adverse drug reactions were assessed using a standardized questionnaire. Fourty-four women experienced side effects, of which 81% were rated by patients as being mild. Patient compliance was higher with the twice daily than with the four times daily regimen: 85% versus 65% prescribed doses taken (P<0.05). There was no significant difference in compliance comparing patients with and without adverse reactions (82% versus 72%, respectively), but compliance was lower and more irregular with at least 3 versus one or two adverse reactions reported: 54% versus 84% in administration compliance and 31% versus 58% in regimen compliance (P<0.05). Compliance was also lower in patients with nausea and vomiting than in those without these symptoms, 59% versus 91% and 34% versus 66% (P<0.005), respectively, and lower with moderate or severe compared to mild side effects; 48% versus 85% and 25% versus 59% (P<0.005). Thus the mere occurrence of side effects was not associated with low compliance. However, the number and nature of symptoms and their intensity as perceived by patients may have considerably influenced drug use behavior.Abbreviations ADR adverse drug reactions - SCMPT sperm cervical mucus penetration-test Prof. Dr. E. Weber died 7 December 1992     

Minimal inhibitory concentration (MIC) of caspofungin and itraconazole inhibiting growth of Candida strains calculated from the linear regression equation

PurposeThe aim of the study was to compare the susceptibility of Candida species to caspofungin and itraconazole.Material and methods118 strains of Candida species were used in the study: 8 pattern strains and 110 strains isolated from different ontocenoses. The susceptibility of fungi strains to drugs was determined by diffusion in agar gel. The minimal inhibitory concentration (MIC) was calculated from the linear regression equation with the use of the method by Kad?ubowski.ResultsThe MIC value for caspofungin for the pattern strains ranged from 0.321 mg/L to 0.552 mg/L and for itraconazole from 0.019 mg/L to 0.11 mg/L. All the analyzed strains isolated from patients exhibited susceptibility to caspofungin; 5 strains of Candida albicans (8.06%) proved to be resistant to itraconazole. The MIC values for caspofungin ranged from 0.114 mg/L to 1.26 mg/L and for itraconazole from 0.012 mg/L to 16.1 mg/L.Conclusions1. All the studied pattern strains are susceptible to the examined drugs; all those isolated from patients show susceptibility to caspofungin; some Candida albicans strains (8.06%) are resistant to itraconazole. 2. The mean MIC values calculated from the activity curves are 0.426 mg/L for caspofungin and 1.0245 mg/L for itraconazole. 3. The mean MIC values calculated for caspofungin are lower than for itraconazole in the case of Candida albicans, C. glabrata and C. tropicalis. Having compared the influence of the drugs on C. famata, C. lusitaniae, C. parapsilosis and C. ciferri we proved there are statistically significant differences (0.0046>p<0.044).     

Vancomycin administration: the impact of multidisciplinary interventions

BACKGROUND: The clinical microbiology team observed that patients were not receiving all prescribed doses of vancomycin. Ward staff was confused about ordering and interpreting vancomycin therapeutic drug monitoring (TDM) levels. AIM: To audit the incidence of vancomycin dose omission. To implement a series of interventions to improve vancomycin dose administration, and to repeat the audit process to assess these interventions. METHODS: Three prospective audits were conducted to assess the impact of vancomycin TDM on administration of vancomycin. After the first audit, a number of changes in the TDM process were undertaken. After review of the second audit, a senior pharmacist coordinated ward-based pharmacists in assisting staff to interpret levels, and TDM interpretative charts were designed for drug charts. Following the third audit, feedback to hospital management and a plan for ongoing education were undertaken. RESULTS: There was a significant reduction in the number of vancomycin doses held inappropriately in the third (10% (78/782) of prescribed doses) when compared to the first audit (16% (161/1007) of doses) (p<0.01). Of doses that were held inappropriately, there was a significant decrease in doses held for no apparent reason in audit 3 (16% (27/170) of prescribed doses) when compared to audit 1 (25% (69/282) of doses) (p<0.05). CONCLUSIONS: The interventions resulted in a 37.5% reduction in inappropriately held vancomycin doses over a one-year period; 10% of doses are still being held inappropriately. This study highlights the difficulties in identifying barriers to change and changing healthcare worker behaviour.     

Computing with evidence: Part II: An evidential approach to predicting metabolic drug–drug interactions

We describe a novel experiment that we conducted with the Drug Interaction Knowledge-base (DIKB) to determine which combinations of evidence enable a rule-based theory of metabolic drug–drug interactions to make the most optimal set of predictions. The focus of the experiment was a group of 16 drugs including six members of the HMG-CoA-reductase inhibitor family (statins). The experiment helped identify evidence-use strategies that enabled the DIKB to predict significantly more interactions present in a validation set than the most rigorous strategy developed by drug experts with no loss of accuracy. The best-performing strategies included evidence types that would normally be of lesser predictive value but that are often more accessible than more rigorous types. Our experimental methods represent a new approach to leveraging the available scientific evidence within a domain where important evidence is often missing or of questionable value for supporting important assertions.     

体外研究人细胞色素P450 3A4等位基因多态性对药物代谢和药物相互作用的影响

 目的 体外研究药物对人细胞色素 P450 3A4（CYP3A4）（野生型，WT）及其 4 个突变等位基因重组酶 CYP3A4*3（M445T）、CYP3A4*4（I118V）、CYP3A4*17（F189S）和CYP3A4*18（L293P）的抑制程度。 方法 采用荧光高通量法和 HPLC 法分别测定 WT 及其 4 个突变等位基因重组酶催化荧光底物——二甲基荧光素（DBF）脱烷基化和探针底物——硝苯地平氧化反应时的酶动力学参数；且通过测定大扶康、万络、西乐葆、酮康唑、地尔硫卓和维拉帕米的半数抑制浓度（IC50）值，确定6 种药物对酶的抑制程度。 结果 除 F189S 外，其余 4 种重组酶均能催化DBF 和硝苯地平反应生成相应的产物。各突变等位基因重组酶催化 DBF 反应的 Km 值（亲和力）与 WT 相当，M445T 和 L293P 的内在清除率分别是 WT 的 3.1 和 3.8 倍（P < 0.05），I118V 是 WT 的 1.3 倍（P = 0.1010）。各重组酶催化硝苯地平氧化反应的 Km 值均比 WT 小，I118V 和 L293P 的内在清除率分别是 WT 的 0.7 和 2.6 倍（P < 0.05），M445T 与 WT 相当（P = 0.7676）。6 种药物对各重组酶的抑制程度强弱均为：酮康唑 > 地尔硫卓 > 维拉帕米 > 大扶康 > 西乐葆 > 万络；药物对各重组酶的 IC50 值大小为：WT < L293P < M445T < I118V。 结论 等位基因突变导致了酶动力学特征的改变和药物对酶抑制程度的不同，为进一步研究临床联合用药安全性奠定基础。     

Quantitative dynamic nuclear polarization‐NMR on blood plasma for assays of drug metabolism

Analytical platforms for the fast detection, identification and quantification of circulating drugs with a narrow therapeutic range are vital in clinical pharmacology. As a result of low drug concentrations, analytical tools need to provide high sensitivity and specificity. Dynamic nuclear polarization‐NMR (DNP‐NMR) in the form of the hyperpolarization–dissolution method should afford the sensitivity and spectral resolution for the direct detection and quantification of numerous isotopically labeled circulating drugs and their metabolites in single liquid‐state NMR transients. This study explores the capability of quantitative in vitro DNP‐NMR to assay drug metabolites in blood plasma. The lower limit of detection for the anti‐epileptic drug ¹³C‐carbamazepine and its pharmacologically active metabolite ¹³C‐carbamazepine‐10,11‐epoxide is 0.08 µg/mL in rabbit blood plasma analyzed by single‐scan ¹³C DNP‐NMR. An internal standard is used for the accurate quantification of drug and metabolite. Comparison of quantitative DNP‐NMR data with an established analytical method (liquid chromatography‐mass spectrometry) yields a Pearson correlation coefficient r of 0.99. Notably, all DNP‐NMR determinations were performed without analyte derivatization or sample purification other than plasma protein precipitation. Quantitative DNP‐NMR is an emerging methodology which requires little sample preparation and yields quantitative data with high sensitivity for therapeutic drug monitoring. Copyright © 2010 John Wiley & Sons, Ltd.     

伊曲康唑致不良反应38例文献分析

目的：探讨伊曲康唑致药品不良反应（ADR）的一般规律及特点。方法：查阅《中国医院知识仓库（cHKD）全文期刊库》1994～2009年伊曲康唑致ADR的有关文献32篇（共38例），进行统计、分析。结果：伊曲康唑致ADR在19～60岁发生率较高，多发生于用药后1～7天内（60．53％），临床表现复杂多样，涉及机体多个器官或系统，主要的ADR为药疹及肝功能损害。结论：临床医师、药师应重视伊曲康唑所致ADR，坚持合理用药。     

Antifungal therapeutic drug monitoring: focus on drugs without a clear recommendation

BackgroundThe goal of therapeutic drug monitoring (TDM) is to determine the appropriate exposure of difficult-to-manage medications to optimize the clinical outcomes in patients in various clinical situations. Concerning antifungal treatment, and knowing that this procedure is expensive and time-consuming, TDM is particularly recommended for certain systemic antifungals: i.e., agents with a well-defined exposure–response relationship and unpredictable pharmacokinetic profile or narrow therapeutic index. Little evidence supports the routine use of TDM for polyenes (amphotericin B), echinocandins, fluconazole or new azoles such as isavuconazole, despite the fact that a better understanding of antifungal exposure may lead to a better response.AimsThe aim of this work is to review published pharmacokinetic/pharmacodynamic data on systemically administered antifungals, focusing on those for which monitoring is not routinely recommended by experts.SourcesA MEDLINE search of the literature in English was performed introducing the following search terms: amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, triazoles, caspofungin, micafungin, anidulafungin, echinocandins, pharmacokinetics, pharmacodynamics, and therapeutic drug monitoring. Review articles and guidelines were also screened.ContentThis review collects different pharmacokinetic/pharmacodynamic aspects of systemic antifungals and summarizes recent threshold values for clinical outcomes and adverse events. Although for polyenes, echinocandins, fluconazole and isavuconazole extensive clinical validation is still required for a clear threshold and a routine monitoring recommendation, particular points such as liposome structure or complex pathophysiological conditions affecting final exposure are discussed. For the rest, their better-defined exposure–response/toxicity relationships allow access to useful threshold values and to justify routine monitoring. Additionally, clinical data are needed to better define thresholds that can minimize the development of antifungal resistance.ImplicationsGeneral TDM for all systemic antifungals is not recommended; however, this approach may help to establish an adequate antifungal exposure for a favourable response, prevention of toxicity or development of resistance in special clinical circumstances.