AAPS‐FDA Workshop White Paper: Microdialysis Principles, Application, and Regulatory Perspectives

Chaurasia, Chandra S.; Müller, Markus; Bashaw, Edward D.; Benfeldt, Eva; Bolinder, Jan; Bullock, Ross; Bungay, Peter M.; DeLange, Elizabeth C. M.; Derendorf, Hartmut; Elmquist, William F.; Hammarlund‐Udenaes, Margareta; Joukhadar, Christian; Kellogg, Dean L.; Lunte, Craig E.; Nordstrom, Carl; Rollema, Hans; Sawchuk, Ronald J.; Cheung, Belinda W.Y.; Shah, Vinod P.; Ståhle, Lars; Ungerstedt, Urban; Welty, Devin; Yeo, Helen

doi:10.1177/0091270006299091

Cited by 122 publications

(149 citation statements)

References 58 publications

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“…In lieu of direct measurements, the lung tissue penetration of second-line drugs has been inferred from using serum concentrations to model tissue concentrations and from bronchial alveolar lining fluid (BAL fluid) or epithelial lining fluid (ELF) drug concentrations (33). The technique of microdialysis was first used to measure drug pharmacokinetics in the 1990s, with much of the early work focused on the central nervous system (14). It was not until the last decade that the technique been used to measure the lung penetration of specific drugs.…”

Section: Discussionmentioning

confidence: 99%

“…The no-net-flux method was utilized for calibration (14). The no-netflux method requires fixed drug concentrations (as in our ex vivo tissue samples) and is considered the gold standard for D calibration (19,20).…”

Section: Methodsmentioning

confidence: 99%

“…To evaluate target site penetration of levofloxacin, we utilized the technique of microdialysis (D). The principle of microdialysis is based on the presence of a concentration gradient between two fluid compartments (cavity and D catheter) across a semipermeable membrane (D probe), with concentrations measured from the recovered dialysate fluid (14,15). Microdialysis measures unbound (pharmacologically active) extracellular drug concentrations (15).…”

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confidence: 99%

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Cavitary Penetration of Levofloxacin among Patients with Multidrug-Resistant Tuberculosis

Kempker

Barth

Vashakidze

et al. 2015

Antimicrob Agents Chemother

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A better understanding of second-line drug (SLD) pharmacokinetics, including cavitary penetration, may help optimize SLD dosing. Patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) undergoing adjunctive surgery were enrolled in Tbilisi, Georgia. Serum was obtained at 0, 1, 4, and 8 h and at the time of cavitary removal to measure levofloxacin concentrations. After surgery, microdialysis was performed using the ex vivo cavity, and levofloxacin concentrations in the collected dialysate fluid were measured. Noncompartmental analysis was performed, and a cavitary-to-serum levofloxacin concentration ratio was calculated. Twelve patients received levofloxacin for a median of 373 days before surgery (median dose, 11.8 mg/kg). The median levofloxacin concentration in serum (C max ) was 6.5 g/ml, and it was <2 g/ml in 3 (25%) patients. Among 11 patients with complete data, the median cavitary concentration of levofloxacin was 4.36 g/ml (range, 0.46 to 8.82). The median cavitary/ serum levofloxacin ratio was 1.33 (range, 0.63 to 2.36), and 7 patients (64%) had a ratio of >1. There was a significant correlation between serum and cavitary concentrations (r ‫؍‬ 0.71; P ‫؍‬ 0.01). Levofloxacin had excellent penetration into chronic cavitary TB lesions, and there was a good correlation between serum and cavitary concentrations. Optimizing serum concentrations will help ensure optimal cavitary concentrations of levofloxacin, which may enhance treatment outcomes.T he emergence of multidrug-resistant tuberculosis (MDR-TB) remains a major barrier to global TB control (1). The treatment course for MDR-TB (with resistance to isoniazid and rifampin) consists of 18 to 24 months of second-line antituberculosis drugs (SLDs), including a fluoroquinolone and an injectable agent (amikacin, kanamycin, or capreomycin). A 2009 meta-analysis of MDR-TB treatment outcomes found an overall success rate of 62% with a range of 36 to 79% (2). The most recent World Health Organization (WHO) global TB report reported an overall successful outcome rate of 48%, again with a wide range (3). These data show that we are far from the goal of a Ͼ75% successful outcome treatment rate among MDR-TB patients; however, the broad range of successful outcomes suggests that we may be able to more effectively maximize existing SLD regimens. A better knowledge of how to optimize available SLD regimens could improve outcomes and provide important principles for the efficacious use of new drugs.The clinical pharmacology of SLDs has been a neglected area of research (4). Pharmacokinetic studies among patients with drugsusceptible TB demonstrate that low concentrations of first-line drugs are associated with poor clinical outcomes, and simulation studies have found that even with perfect adherence up to 1% of patients would develop further drug resistance during treatment due to variability in drug concentrations (5-7). A recent report on 25 patients with MDR-TB found that plasma SLD concentrations were frequently low and were associated with decreased drug ...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Cavitary Penetration of Levofloxacin among Patients with Multidrug-Resistant Tuberculosis

Kempker

Barth

Vashakidze

et al. 2015

Antimicrob Agents Chemother

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“…The technique of in vivo D, previously described in numerous review articles, has become an established method for the description of tissue pharmacokinetics, especially in the field of drug distribution and metabolism (9)(10)(11). In brief, this method is based on the exchange of analytes between the extracellular space fluid (ECF) of the tissue or compartment of interest and the perfusion fluid of a D probe.…”

Section: Methodsmentioning

confidence: 99%

“…To determine the actual ECF concentration, D probes must be calibrated. In this study, each single probe was calibrated by reverse dialysis, also referred to as retrodialysis (9). The retrodialysis method relies on the fact that the process of diffusion across the semipermeable membrane is quantitatively equal in both directions.…”

Section: Methodsmentioning

confidence: 99%

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

Matzneller

Lackner

Lagler

et al. 2016

Antimicrob Agents Chemother

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bCeftaroline fosamil (CPT-F) is currently approved for use for the treatment of complicated skin and soft tissue infections and community-acquired pneumonia at 600 mg twice daily (q12h), but other dosing regimens are under evaluation. To date, very limited data on the soft tissue pharmacokinetics (PK) of the active compound, ceftaroline (CPT), are available. CPT concentrations in the plasma, muscle, and subcutis of 12 male healthy volunteers were measured by microdialysis after single and repeated intravenous administration of 600 mg CPT-F q12h or three times daily (q8h) in two groups of 6 subjects each. Relevant PK and PK/pharmacodynamic (PD) parameters were calculated and compared between groups. In plasma, the area under the concentration-time curve (AUC) from 0 to 24 h for total CPT and the cumulative percentage of the dosing interval during which the free drug concentrations exceeded the MIC (fT MIC ) for unbound CPT for the currently established threshold of 1 mg/liter were significantly higher in the group receiving CPT-F q8h. Exposure to free drug in soft tissues was higher in the group receiving CPT-F q8h, but high interindividual variability in relevant PK parameters was observed. The mean ratios of the AUC from time zero to the end of the dosing interval (AUC 0-) for free CPT in soft tissues and the AUC 0-for the calculated free fraction in plasma at steady state ranged from 0.66 to 0.75. Administration of CPT-F q8h led to higher levels of drug exposure in all investigated compartments. When MIC values above 1 mg/liter were assumed, the calculated fT MIC after dosing q12h was markedly lower than that after dosing q8h. The clinical implications of these differences are discussed in light of recently completed clinical phase III and PK/PD studies. Ceftaroline fosamil (CPT-F; brand names, Zinforo in Europe and Teflaro in the United States) was recently approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of complicated skin and soft tissue infections (cSSTIs) and community-acquired pneumonia (CAP) in adults. Ceftaroline (CPT) is a cephalosporin antibiotic and acts, like all beta-lactam agents, via inhibition of peptidoglycan synthesis. In contrast to other cephalosporins, CPT is active against some resistant microorganisms, such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-nonsusceptible Streptococcus pneumoniae (PNSP), and is therefore often referred to as a "fifth generation," or advanced-generation, cephalosporin. CPT-F, a water soluble N-phosphono prodrug, is converted to the active CPT in human plasma, and CPT is further converted into the inactive ring-opened metabolite CPT M-1.Although CPT-F was shown to be effective against both approved indications, CAP and cSSTIs (1-5), precise information regarding the pharmacokinetics (PKs) of CPT in the interstitial space fluid of soft tissues is very limited to date. However, this information is considered to be highly relevant as a key input for PK/pharmacodynamic (PD) cal...

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Overview of Experimental Models of the Blood‐Brain Barrier in CNS Drug Discovery

Palmer¹,

Alavijeh

2013

CP Pharmacology

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The blood-brain barrier (BBB) is a physical and metabolic entity that isolates the brain from the systemic circulation. The barrier consists of tight junctions between endothelial cells that contain egress transporters and catabolic enzymes. To cross the BBB, a drug must possess the appropriate physicochemical properties to achieve a sufficient time-concentration profile in brain interstitial fluid (ISF). In this overview, we review techniques to measure BBB permeation, which is evidenced by the free concentration of compound in brain ISF over time. We consider a number of measurement techniques, including in vivo microdialysis and brain receptor occupancy following perfusion. Consideration is also given to the endothelial and nonendothelial cell systems used to assess both the BBB permeation of a test compound and its interactions with egress transporters, and computer models employed for predicting passive permeation and the probability of interactions with BBB transporters.

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AAPS‐FDA Workshop White Paper: Microdialysis Principles, Application, and Regulatory Perspectives

Cited by 122 publications

References 58 publications

Cavitary Penetration of Levofloxacin among Patients with Multidrug-Resistant Tuberculosis

Cavitary Penetration of Levofloxacin among Patients with Multidrug-Resistant Tuberculosis

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

Overview of Experimental Models of the Blood‐Brain Barrier in CNS Drug Discovery

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