Drug Removal by Plasmapheresis: An Evidence-Based Review
Drug Removal by Plasmapheresis: An Evidence-Based Review
Contrary to the literature about drug removal during hemodialysis, data regarding drug removal during plasmapheresis are sparse. Over the last 40 years, approximately 70 publicationsmostly case reports of overdoses have described the effects of plasmapheresis on pharmaceutical agents. Important issues are drug extraction during plasma exchange with chemotherapy, as well as drug classes such as antiinfectives, anticoagulants, antiepileptics, cardiovascular agents, and immunosuppressants. Other considerations are the merits and pitfalls of the different methods used in published reports and recommendations for future pharmacokinetic studies in this field.
Plasma exchange, or plasmapheresis, has been used since the early 1970s to treat medical conditions such as thrombotic thrombocytopenic purpura (TTP) in adults and sepsis associated with hyperbilirubinemia in neonates. Its benefit is also well established in autoimmune diseases such as myasthenia gravis, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy. The term apheresis originates from the Greek word aphairesis meaning withdrawal. Plasma exchange is the process of separating plasma from red blood cells and returning the plasma to the body with replacement physiologic fluids, such as albumin or fresh frozen plasma, to maintain oncotic pressure and blood volume.
Elimination by means of plasma exchange is a passive process that can be described with linear kinetics. A single exchange of 1 plasma volume (3 L for a 70-kg patient) removes approximately 63% of all solutes in the plasma and an exchange of 1.5 plasma volume removes about 78%. Under normal circumstances, plasma exchange removes 4060 ml of plasma/kg over 23 hours. Blood components can be separated by filtration, which allows for the removal of all plasma components except red blood cells, or by centrifugation, which allows for the selective removal of cell types (e.g., bone marrowderived stem cells).
Owing to its ability to remove plasma, plasma exchange may eliminate circulating drugs from the plasma compartment. This effect can be adverse, as it may alter the disposition of a drug by lowering its serum concentrations to subtherapeutic levels, or it can be favorable, as in drug overdoses. Plasma exchange may also indirectly affect drug therapy, although actual drug kinetics may not change substantially. An example is the removal of circulating autoantibodies to cholinesterase with plasma exchange, an effect that prolongs the action of anticholinesterase drugs.
In general, drugs with a low volume of distribution (Vd) and/or a high rate of protein binding are most likely to be removed during plasma exchange. Some have proposed that plasma exchange is useful only when plasma protein binding of a substance is greater than 80% and when the Vd is less than 0.2 L/kg. That stated, others have included the exchanged plasma volume, intercompartment equilibration, and endogenous clearance as important determinants of the ability of plasma exchange to remove a given drug. Of note, removal of drugs with plasma exchange might be compared to the removal of immunoglobulin M; however, this suggestion was validated in only one report.
These 30-year-old prevailing concerns about drug removal by plasma exchange have not translated into an extensive repository of published research. Only about 70 publicationsmostly case reports of overdose or exploratory ingestionsare available. Sixteen (23%) of these publications are reports from formal pharmacokinetic studies. Authors of a review article stated that the number of controlled studies conducted to evaluate extracorporeal drug elimination during plasma exchange will expand dramatically. This prediction has not proven true so far.
In the existing body of literature, almost all reports are heterogeneous in that they describe differences (e.g., in duration, volume, or replacement fluid) among plasma exchange procedures. Furthermore, lack of uniformity in sampling times (e.g., drug administration time vis-à-vis the start of plasma exchange), use of different analyses to ascertain removal (decline in the drug plasma concentration during plasma exchange vs the total quantity of drug removed from the plasma), statistical flaws, and inappropriate extrapolation to other patient populations (adults vs neonates) all hamper meaningful generalization of the results into everyday clinical practice.
Given the dearth of information spanning almost 4 decades, we undertook an evidence based review of the literature that reports drug disposition during plasma exchange. Our objectives were to spur interest in this pharmacokinetic area untapped by practitioners and academicians, to draft criteria based on the existing evidence for the optimal design of trials assessing drug removal by plasma exchange, and, when possible, to provide a dosing tool based on the available literature for clinicians to use during plasma exchange
( Table 1 ).
We conducted a PubMed-MEDLINE database search of the clinical literature (1996November 2006). All plasma exchange drug-removal case reports, case series, and clinical trials in humans published in English, German, Italian, or French were evaluated. Their information was categorized according to drug class.
Contrary to the literature about drug removal during hemodialysis, data regarding drug removal during plasmapheresis are sparse. Over the last 40 years, approximately 70 publicationsmostly case reports of overdoses have described the effects of plasmapheresis on pharmaceutical agents. Important issues are drug extraction during plasma exchange with chemotherapy, as well as drug classes such as antiinfectives, anticoagulants, antiepileptics, cardiovascular agents, and immunosuppressants. Other considerations are the merits and pitfalls of the different methods used in published reports and recommendations for future pharmacokinetic studies in this field.
Plasma exchange, or plasmapheresis, has been used since the early 1970s to treat medical conditions such as thrombotic thrombocytopenic purpura (TTP) in adults and sepsis associated with hyperbilirubinemia in neonates. Its benefit is also well established in autoimmune diseases such as myasthenia gravis, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy. The term apheresis originates from the Greek word aphairesis meaning withdrawal. Plasma exchange is the process of separating plasma from red blood cells and returning the plasma to the body with replacement physiologic fluids, such as albumin or fresh frozen plasma, to maintain oncotic pressure and blood volume.
Elimination by means of plasma exchange is a passive process that can be described with linear kinetics. A single exchange of 1 plasma volume (3 L for a 70-kg patient) removes approximately 63% of all solutes in the plasma and an exchange of 1.5 plasma volume removes about 78%. Under normal circumstances, plasma exchange removes 4060 ml of plasma/kg over 23 hours. Blood components can be separated by filtration, which allows for the removal of all plasma components except red blood cells, or by centrifugation, which allows for the selective removal of cell types (e.g., bone marrowderived stem cells).
Owing to its ability to remove plasma, plasma exchange may eliminate circulating drugs from the plasma compartment. This effect can be adverse, as it may alter the disposition of a drug by lowering its serum concentrations to subtherapeutic levels, or it can be favorable, as in drug overdoses. Plasma exchange may also indirectly affect drug therapy, although actual drug kinetics may not change substantially. An example is the removal of circulating autoantibodies to cholinesterase with plasma exchange, an effect that prolongs the action of anticholinesterase drugs.
In general, drugs with a low volume of distribution (Vd) and/or a high rate of protein binding are most likely to be removed during plasma exchange. Some have proposed that plasma exchange is useful only when plasma protein binding of a substance is greater than 80% and when the Vd is less than 0.2 L/kg. That stated, others have included the exchanged plasma volume, intercompartment equilibration, and endogenous clearance as important determinants of the ability of plasma exchange to remove a given drug. Of note, removal of drugs with plasma exchange might be compared to the removal of immunoglobulin M; however, this suggestion was validated in only one report.
These 30-year-old prevailing concerns about drug removal by plasma exchange have not translated into an extensive repository of published research. Only about 70 publicationsmostly case reports of overdose or exploratory ingestionsare available. Sixteen (23%) of these publications are reports from formal pharmacokinetic studies. Authors of a review article stated that the number of controlled studies conducted to evaluate extracorporeal drug elimination during plasma exchange will expand dramatically. This prediction has not proven true so far.
In the existing body of literature, almost all reports are heterogeneous in that they describe differences (e.g., in duration, volume, or replacement fluid) among plasma exchange procedures. Furthermore, lack of uniformity in sampling times (e.g., drug administration time vis-à-vis the start of plasma exchange), use of different analyses to ascertain removal (decline in the drug plasma concentration during plasma exchange vs the total quantity of drug removed from the plasma), statistical flaws, and inappropriate extrapolation to other patient populations (adults vs neonates) all hamper meaningful generalization of the results into everyday clinical practice.
Given the dearth of information spanning almost 4 decades, we undertook an evidence based review of the literature that reports drug disposition during plasma exchange. Our objectives were to spur interest in this pharmacokinetic area untapped by practitioners and academicians, to draft criteria based on the existing evidence for the optimal design of trials assessing drug removal by plasma exchange, and, when possible, to provide a dosing tool based on the available literature for clinicians to use during plasma exchange
( Table 1 ).
We conducted a PubMed-MEDLINE database search of the clinical literature (1996November 2006). All plasma exchange drug-removal case reports, case series, and clinical trials in humans published in English, German, Italian, or French were evaluated. Their information was categorized according to drug class.
