This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients.
 Literature review and analysis were performed by Panel Members nominated by the endorsing organisations, European Society of Intensive Care Medicine (ESICM), Pharmacokinetic/Pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID), International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) and International Society of Antimicrobial Chemotherapy (ISAC). Panel members made recommendations for whether TDM should be applied clinically for different antimicrobials/classes. TDM-guided dosing has been shown to be clinically beneficial for aminoglycosides, voriconazole and ribavirin. For most common antibiotics and antifungals in the ICU, a clear therapeutic range has been established, and for these agents, routine TDM in critically ill patients appears meritorious. For the antivirals, research is needed to identify therapeutic targets and determine whether antiviral TDM is indeed meritorious in this patient population. The Panel Members recommend routine TDM to be performed for aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin and voriconazole in critically ill patients. Although TDM should be the standard of care for most antimicrobials in every ICU, important barriers need to be addressed before routine TDM can be widely employed worldwide.

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Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper .

// David M. Goldenberg 1 , Thomas M. Cardillo 1 , Serengulam V. Govindan 1 , Edmund A. Rossi 1 , Robert M. Sharkey 1 1 Immunomedics, Inc., Morris Plains, NJ, USA * Presented in part as a lecture by DMG, “Challenging the Dogmas: Clinical Efficacy of SN-38-conjugated Antibodies in Solid Tumors,” at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapy, Barcelona, Spain, November 20, 2014. Correspondence to: David M. Goldenberg, e-mail: dmg.gscancer@att.net Keywords: antibody-drug conjugate, Trop-2, SN-38, solid cancers, triple-negative breast cancer Received: April 28, 2015      Accepted: June 05, 2015      Published: June 18, 2015 ABSTRACT Trop-2 is a novel target for ADC therapy because of its high expression by many solid cancers. The rational development of IMMU-132 represents a paradigm shift as an ADC that binds a well-known moderately-cytotoxic drug, SN-38, to the anti-Trop-2 antibody. In vitro and in vivo studies show enhanced efficacy, while there is a gradual release of SN-38 that contributes to the overall effect. IMMU-132 is most efficacious at a high drug:antibody ratio (DAR) of 7.6:1, which does not affect binding and pharmacokinetics. It targets up to 136-fold more SN-38 to a human cancer xenograft than irinotecan, SN-38′s prodrug. IMMU-132 delivers SN-38 in its most active, non-glucuronidated form, which may explain the lower frequency of severe diarrhea than with irinotecan. Thus, this ADC, carrying a moderately-toxic drug targeting Trop-2 represents a novel cancer therapeutic that is showing promising activity in patients with several metastatic cancer types, including triple-negative breast cancer, non-small-cell and small-cell lung cancers.

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Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC)

Adverse drug-drug interactions are a major cause of morbidity and mortality. Cancer patients are at particularly high risk of such interactions because they commonly receive multiple medications, including cytotoxic chemotherapy, hormonal agents and supportive care drugs. In addition, the majority of cancer patients are elderly, and so require medications for co-morbid conditions such as cardiovascular, gastrointestinal, and rheumatological diseases. Furthermore, the age-related decline in hepatic and renal function reduces their ability to metabolize and clear drugs and so increases the potential for toxicity. Not all drug-drug interactions can be predicted, and those that are predictable are not always avoidable. However, increased awareness of the potential for these interactions will allow healthcare providers to minimize the risk by choosing appropriate drugs and also by monitoring for signs of interaction. This review considers the basic principles of drug-drug interactions, and presents specific examples that are relevant to oncology.

Drug–drug interactions in oncology: Why are they important and can they be minimized?

Objectives This review discusses the limitations and applications of the everted gut sac model in studying drug absorption, metabolism, and interaction.



Key findings  The mechanism of drug absorption, interaction and the effect of factors such as age, sex, species, chronic therapy, and disease state on drug absorption have been summarized. The experimental conditions and their effects on the outcomes of trials have been discussed also.



Summary  The everted sac model is an efficient tool for studying in-vitro drug absorption mechanisms, intestinal metabolism of drugs, role of transporter in drug absorption, and for investigating the role of intestinal enzymes during drug transport through the intestine.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.2042-7158.2011.01391.x

Everted gut sac model as a tool in pharmaceutical research: limitations and applications

Lassa fever is an acute viral hemorrhagic illness; the virus is endemic in West Africa and also of concern with regard to bioterrorism. Transmission of Lassa virus between humans may occur through direct contact with infected blood or bodily secretions. Oral administration of the antiviral drug ribavirin is often considered for postexposure prophylaxis, but no systematically collected data or uniform guidelines exist for this indication. Furthermore, the relatively low secondary attack rates for Lassa fever, the restriction of the area of endemicity to West Africa, and the infrequency of high-risk exposures make it unlikely that controlled prospective efficacy trials will ever be possible. Recommendations for postexposure use of ribavirin can therefore be made only on the basis of a thorough understanding and logical extrapolation of existing data. Here, we review the pertinent issues and propose guidelines based on extensive review of the literature, as well as our experience in this field. We recommend oral ribavirin postexposure prophylaxis for Lassa fever exclusively for definitive high-risk exposures. These guidelines may also serve for exposure to other hemorrhagic fever viruses susceptible to ribavirin.

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Review of the Literature and Proposed Guidelines for the Use of Oral Ribavirin as Postexposure Prophylaxis for Lassa Fever

The daily dose of ribavirin is currently 1 determined based on body weight. In the present study, the authors examined factors influencing total plasma clearance (CL t o t a l ) and the toxic level on red blood cells of ribavirin in such body weight-based dosage adjustment in Japanese chronic hepatitis C patients (13 male and 6 female). Patients received ribavirin (600 or 800 mg/d) orally, depending on their body weights, together with interferon α-2b (6 million units) intramuscularly. A steady-state trough plasma concentration (C p s s ) was achieved approximately 4 weeks after the initiation of treatment, but the value was scattered among patients in a range from 1100 to 4200 ng/mL. The high C p s s of ribavirin of approximately 4000 ng/mL decreased hemoglobin concentrations to less than 8.5 g/dL. The individual CL t o t a l , estimated by dividing dose normalized by body weight by C p s s , of ribavirin correlated significantly with the patient's creatinine clearance. In contrast, no relationship was observed with other parameters such as age, body weight, serum creatinine concentration, alanine aminotransferase (ALT) concentration, or aspartate aminotransferase (AST) concentration, though ALT and AST concentrations decreased with ribavirin treatment in most patients. These results indicate that CL t o t a l of ribavirin is dependent on renal function (creatinine clearance), and hemolysis is induced by high ribavirin concentrations in plasma. Dosage adjustment of ribavirin based on renal function and body weight would provide effective and safer treatment without causing hemolysis.

Dosage adjustment of ribavirin based on renal function in Japanese patients with chronic hepatitis C.

In irinotecan (CPT-11)-based chemotherapy, neutropenia and diarrhea are often induced. In the present study, the clinical significance of the concentration ratios of 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronide (SN-38G) and SN-38 in the plasma in predicting CPT-11-induced neutropenia was examined. A total of 17 patients with colorectal cancer and wild-type UDP-glucuronosyltransferase (UGT)1A1 gene were enrolled and treated with CPT-11 as part of the FOLFIRI regimen [CPT-11 and fluorouracil (5-FU)]. Blood was taken exactly 15 min following a 2-h continuous infusion of CPT-11. Plasma concentrations of SN-38, SN-38G and CPT-11 were determined by a modified high-performance liquid chromatography (HPLC) method. The median, maximum and minimum values of plasma SN-38G/SN-38 ratios were 4.25, 7.09 and 1.03, respectively, indicating that UGT activities are variable among patients with the wild-type UGT1A1 gene. The plasma SN-38G/SN-38 ratios decreased with an increase in the trial numbers of chemotherapy (r=0.741, p=0.000669), suggesting that CPT-11 treatment suppresses UGT activity, and the low plasma SN-38G/SN-38 ratios resulted in the induction of greater neutropenia. However, in this analysis, 2 clearly separated regression lines were observed between plasma SN-38G/SN-38 ratios and neutropenia induction. In conclusion, UGT activity involved in SN-38 metabolism is variable among patients with the wild-type UGT1A1 gene, and each CPT-11 treatment suppresses UGT activity. One-point determination of the plasma SN-38G/SN-38 ratio may provide indications for the prediction of CPT-11-induced neutropenia and adjustment of the optimal dose, although further studies are required.

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Correlation between plasma concentration ratios of SN-38 glucuronide and SN-38 and neutropenia induction in patients with colorectal cancer and wild-type UGT1A1 gene

Increased erythrocyte distribution of valproic acid in pharmacokinetic interaction with carbapenem antibiotics in rat and human

We newly synthesized a pivaloyloxymethyl ester of ofloxacin (OFLX-PVM) as prodrug in order to avoid the chelate formation between new quinolone and metal cations such as Al3+, Mg2+, Ca2+, or Fe2+ in the gastrointestinal tract. This compound was rapidly hydrolyzed in an incubation experiment by 43% in plasma, by 92% in small intestinal mucosal homogenates, and by 97% in liver homogenates during 0.5 h incubation, but was resistant to hydrolysis by pancreatic enzymes. In everted gut sac experiments, this compound was efficiently absorbed even in the presence of aluminium ion, whereas the absorption of ofloxacin (OFLX) was decreased significantly by the presence of aluminium ion. Minimal inhibitory concentration (MIC) values of OFLX-PVM were far higher than OFLX. Effects of aluminium hydroxide on the oral bioavailability of OFLX and OFLX-PVM were investigated in rabbits. The area under the plasma concentration-versus-time curve from zero to 24 h (AUC0-24h) following oral administration of OFLX was decreased significantly by 47.6% by combined administration with aluminium hydroxide, but AUC0-24h values of OFLX-PVM coadministered with and without aluminium hydroxide were similar to that of OFLX alone. These observations indicate that this new compound is likely to offer a prodrug for avoidance of interaction between new quinolone and metal cations.

Effects of aluminium-containing antacid on bioavailability of ofloxacin following oral administration of pivaloyloxymethyl ester of ofloxacin as prodrug

Kei Omoda

Papers

Dosage adjustment of ribavirin based on renal function in Japanese patients with chronic hepatitis C.

Correlation between plasma concentration ratios of SN-38 glucuronide and SN-38 and neutropenia induction in patients with colorectal cancer and wild-type UGT1A1 gene

Increased erythrocyte distribution of valproic acid in pharmacokinetic interaction with carbapenem antibiotics in rat and human

Effects of aluminium-containing antacid on bioavailability of ofloxacin following oral administration of pivaloyloxymethyl ester of ofloxacin as prodrug

Evaluation of clinical efficacy of Maeda's nomogram for vancomycin dosage adjustment in adult Japanese MRSA pneumonia patients.