Medications and therapeutic apheresis procedures: are we doing our best?

Therapeutic apheresis refers to a group of extracorporeal therapies commonly used in the treatment of a variety of neurological, renal, hematological, and other systemic diseases caused by circulating "toxic agents" that cannot be cleared by other means. This article presents an overview of the concepts underlying the effect of therapeutic apheresis procedures on prescription drugs taken by patients and describes key drug-related and procedure-related factors that may impact drug disposition during therapeutic apheresis. Therapeutic apheresis, and specifically therapeutic plasma exchange (TPE), is the process involving the extracorporeal separation of plasma from the cellular components of blood, discarding the plasma and exchanging it with replacement physiologic fluids such as albumin or fresh frozen plasma to maintain oncotic pressure and blood volume, and then returning this and the original cellular components of blood back to the patient's circulatory system (Ibrahim and Balogun, Semin Dial 2012;25:176-189). Over the last 4 decades, modern therapeutic apheresis has been used clinically for the treatment of a host of renal, hematological, and neurological diseases such as Goodpasture's syndrome, thrombotic thrombocytopenic purpura, and myasthenia gravis to name a few (Ibrahim et al., Pharmacotherapy 2007;27:1529-1549). Because of its ability to remove plasma, TPE can extract circulating drugs residing in this compartment, thereby affecting their disposition and potentially their therapeutic action (Ibrahim and Balogun, Semin Dial 2012;25:176-189; Ibrahim et al., Pharmacotherapy 2007;27:1529-1549; Kale-Pradhan and Woo, Pharmacotherapy 1997;17:684-695; Kintzel et al., J Clin Apher 2003;18:194-205). The aim of this article is to shed light on drug-related and TPE-related factors that may influence drug removal by TPE. Emphasis is put on areas needing improvement in the way of assessing drug removal by TPE. In addition, a call for an expanded investigation of TPEs influence on select compounds is enlisted.

Medications in patients treated with therapeutic plasma exchange: prescription dosage, timing, and drug overdose.

Therapeutic plasma exchange (TPE) is an extracorporeal process commonly used in clinical medicine for the treatment of a variety of neurological, renal, hematological, dermatological, and other diseases. Inherent to the procedure, patients' plasma removal may lead to the extraction of drugs they are concurrently receiving. This review discusses the published literature assessing TPE's influence on different drug classes' disposition and, when applicable, sets forth management recommendations in cases where the drugs are used at the usual doses and in cases of drug overdose.

Dapsone-induced methemoglobinemia: a primer for clinicians.

OBJECTIVE: To present a comprehensive review of dapsone-induced methemoglobinemia and its management. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1966-March 2011), Cochrane Library, and EMBASE, using the terms dapsone and methemoglobinemia. STUDY SELECTION AND DATA EXTRACTION: All case reports, small case series, and randomized controlled trials published in English were evaluated. Because of the absence of comprehensive updates on this topic since 1996, publications between 1997 and March 2011 were included in this review. DATA SYNTHESIS: Between 1997 and March 2011, the majority of publications describing methemoglobinemia associated with dapsone use reported this adverse effect at therapeutic doses. Excluding overdose situations, 18 described symptomatic dapsone-associated methemoglobinemia and clinical presentation ranging from cyanosis to dyspnea. In almost all of the accounts, patients had a concurrent event such as anemia or pneumonia, suggesting an interplay between these comorbidities and the onset of symptomatic methemoglobinemia. Delayed hemolytic anemia was seen in patients with high methemoglobin levels at presentation. Management in most cases consisted of administration of methylene blue. Overall, most reports described a successful outcome, and no mortality resulted from methemoglobinemia associated with therapeutic use. CONCLUSIONS: Clinicians should recognize methemoglobinemia as an adverse effect associated with dapsone use and the potential factors that precipitate it. They should also know how to promptly and effectively manage this event.

Nonabsorbable corticosteroids use in the treatment of gastrointestinal graft-versus-host disease.

For over a decade, nonabsorbable corticosteroids have been employed in the treatment of gastrointestinal graft-versus-host-disease (GVHD) in hematopoietic stem cell transplant (HSCT), as monotherapy or in combination with systemic corticosteroids. The majority of the evidence showing a favorable outcome consisted of case series, small phase II trials and a large randomized phase III trial. The 2 most commonly studied molecules were oral budesonide and beclomethasone diproprionate. Although these reports hint at some benefit with the local treatment strategy, their methodologic inconsistencies preclude meaningful adoption to everyday clinical practice. This review evaluates the current evidence of nonabsorbable corticosteroids in HSCT and sets forth recommendations for future trials with these agents.

Influence of plasma exchange on the disposition of the fourth generation cephalosporin cefepime.

Cefepime, a fourth generation cephalosporin, is widely used in hematology and oncology patients. These patients may require plasma exchange (PE) for indications such as chemotherapy- or cancer-induced thromobotic thrombocytopenic purpura to name a few. To date, no pharmacokinetic evaluation has been conducted assessing cefepime's disposition during PE. A 2 g IV cefepime single dose was given to patients undergoing therapeutic PE. Two hours from cefepime dose administration, plasma concentration was measured. PE was then instituted and cefepime plasmapheresate concentration was measured at the completion of the PE session. Cefepime levels were measured using HPLC. The percentage removed by PE was calculated as: amount removed/2 g dose. Ten adult patients were analyzed: median age (range): 52 years (33-67) and median weight (range); 82.85 kg (47-120). PE indications were: myasthenia gravis (n = 3), transverse myelitis (n = 2), multiple sclerosis (n = 1), chronic inflammatory demyelinating polyneuropathy (n = 1), idiopathic thrombocytopenic purpura (n = 1), thrombotic thrombocytopenic purpura (n = 1), and humoral rejection post cadaveric renal allograft (n = 1). All patients except one had a creatinine clearance >60 mL/min. One patient was excluded from the pharmacokinetic analysis owing to loss of venous access during PE. For the remaining nine patients, total plasma volume removed was 3.5 L (range: 2.5-3.5) and duration of PE was 120 min (range: 94-209). The cefepime removed by PE was 3.7% (range: 2.1-6.7). A strong correlation was found between cefepime plasma concentration prior to PE and the amount of drug removed (r = 0.96, r(2) = 0.92; p<0.05). The above results suggest that, under the studied conditions, cefepime removal by PE is clinically insignificant (approximately 4% of total 2 g dose).

Early intervention with antithrombin III therapy to prevent progression of hepatic venoocclusive disease.

Venoocclusive disease (VOD) is the most frequent cause of early nonrelapse mortality among patients receiving high-dose chemoradiotherapy and hematopoietic stem cell transplantation. Endothelial injury of sinusoids and hepatic veins following chemotherapy is considered the initial event in the development of VOD. Activation of the coagulation cascade and inflammatory processes following endothelial injury results in a hypercoagulable state and a localized consumption of the natural anticoagulants, antithrombin III, protein C and protein S. The resultant coagulopathy can lead to multiorgan dysfunction and death. The objective was to retrospectively study the largest series of patients that has received antithrombin III for the treatment of VOD following hematopoietic stem cell transplantation. A total of 48 patients were diagnosed with VOD post hematopoietic stem cell transplantation (median age, 39 years; range, 1-69 years); 38 of the 48 received a nonradiation-based conditioning regimen and 21 of 48 received a transplant from an unrelated donor. Treatment was primarily directed at early intervention rather than prophylactic therapy to correct the antithrombin III deficiency associated with VOD. We attempted to achieve antithrombin III levels greater than 120%. There was no significant treatment-related morbidity. The overall 100-day mortality for the treatment cohort was 17%, with 10% for the mild/moderate group and 39% for the severe group, respectively. In conclusion, the encouraging results of this study suggest that this antithrombin III treatment should be further considered in patients with severe VOD.

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 publications-mostly 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.

Sirolimus-itraconazole interaction in a hematopoietic stem cell transplant recipient.

Interactions between azole antifungal agents and immunosuppressants that are metabolized by cytochrome P450 3A4 (chiefly calcineurin inhibitors) are well documented. Interactions between itraconazole and sirolimus are known to occur in patients after solid organ transplantation, but interactions in hematopoietic stem cell transplant (HSCT) recipients have yet to be reported in the literature. We describe an allogeneic HSCT recipient who experienced supratherapeutic trough levels of sirolimus as a result of its coadministration with itraconazole. This patient was a 20-year-old African-American man who underwent HSCT for treatment of myelodysplastic syndrome with severe aplastic anemia. After several regimen changes, the patient received oral itraconazole 200 mg every 12 hours and sirolimus at a dosage of 7 mg/day on days 76-80 and 5 mg/day on days 81 and 82. His sirolimus whole blood trough levels were 17.5 and 35.6 ng/ml on days 80 and 82, respectively (therapeutic range 5-15 ng/ml). An interaction between itraconazole and sirolimus was suspected, and sirolimus was withheld on days 83-90. On day 90, the patient's sirolimus trough level had normalized to 4.4 ng/ml. Sirolimus was resumed at 1-2 mg/day, with adjustments as needed to maintain trough levels of 10-15 ng/ml. Both the itraconazole and sirolimus were eventually were discontinued. The patient died, however, from a disseminated adenovirus infection leading to end-organ failure. Sirolimus is extremely sensitive to the inhibitory potential of azole antifungals. We propose that itraconazole also has a potent effect on sirolimus metabolism. Preemptive sirolimus dosage reduction and close monitoring of its whole blood trough levels are required whenever this combination is considered to avoid immunosuppressant toxicity in already critically ill patients.

'Sailing in troubled waters': a review of the use of anticoagulation in adult cancer patients with thrombocytopenia.

Simply providing anticoagulation therapy is not as straightforward of a solution in cancer patients who have concurrent thrombocytopenia owing to the increased risk of bleeding complications. Currently, few guidelines are in place to assist clinicians in safely managing thrombocytopenic cancer patients on anticoagulation. The purpose of this review is to critically examine the available body of biomedical literature surrounding anticoagulant use against the backdrop of cancer-related thrombocytopenia in adult patients. Available evidence for the use of parenteral anticoagulants (low molecular weight heparins, unfractionated heparin, pentasaccharides, and direct thrombin inhibitors) and oral anticoagulants (vitamin K antagonists and novel oral anticoagulants) in thrombocytopenic cancer patients is described. The review revealed many inconsistencies between reports on this topic, which made it difficult to draw firm conclusions as to, for example, the ideal well tolerated anticoagulant dose in thrombocytopenic cancer patients? Intriguingly, critical clinical information including (but not limited) patient platelet nadirs, platelet counts during bleeding episodes, and platelet transfusion support was absent from a not-so-insignificant number of publications. Despite these shortcomings, the review sets out to formulate recommendations on the management of anticoagulation, at prophylactic or treatment doses, in adult cancer patients who also have concurrent thrombocytopenia. It also enlists a call for the medical community, by mapping select clinical guideposts, for further research in this setting. With the inclusion of these criteria in future studies, only then formal recommendations on the ideal safe dosage of anticoagulants in cancer patients, based on solid evidence, are conceived.

Systemic absorption of topical lidocaine in a bone marrow transplant recipient with hepatic sinusoidal obstruction syndrome.

PURPOSE: A case of systemic lidocaine exposure in a bone marrow transplant recipient with severe hepatic sinusoidal obstruction syndrome (SOS) receiving treatment with lidocaine patch 5% is reported. SUMMARY: A 35-year-old Caucasian man with a history of refractory acute lymphoblastic leukemia was admitted for a third allogeneic, mismatched, peripheral blood hematopoietic stem cell transplant from an unrelated donor, with a conditioning regimen that included busulfan and fludarabine. The patient was receiving treatment with lidocaine patch 5% (two patches daily, which was started five months before another hospital admission for the treatment of vincristine-related peripheral neuropathy. Baseline laboratory findings were within normal limits except for disease-related neutropenia and thrombocytopenia. Twenty days after hematopoietic stem cell transplantation (HSCT), the patient developed signs and symptoms of severe hepatic SOS. His serum alanine transaminase concentration rose from 65 IU/L at baseline to 370 IU/L, and his serum aspartate transaminase concentration rose from 32 IU/L at baseline to 871 IU/L. His total bilirubin increased to 2.8 mg/dL, and his body weight increased by 15%. An abdominal ultrasound noted ascites and hepatomegaly without reversal of blood flow. The lidocaine patch was discontinued, but the patient's condition continued to deteriorate. He died 38 days after HSCT from complications of severe hepatic SOS. CONCLUSION: A 35-year-old man developed hepatic SOS 20 days after his third HSCT. As a result of his hepatic impairment, the patient, who had been receiving lidocaine patch 5% for the treatment of neuropathic pain, experienced increased systemic exposure to lidocaine, which led to discontinuation of the patch.

Immediate cross-hypersensitivity between micafungin and caspofungin: a case report.

A hematopoietic stem cell transplant patient with a history of immediate drug hypersensitivity reaction to micafungin was considered for a caspofungin trial. A caspofungin intradermal skin test was performed. The result was positive, suggesting the presence of cross-reactivity and that the cyclic peptide nucleus chemical structure shared between echinocandins is the site of IgE recognition. It is recommended to avoid challenging patients with history of immediate hypersensitivity to one echinocandin with another.

Effect of aprepitant on intravenous tacrolimus disposition in reduced intensity hematopoietic stem cell transplantation.

Aprepitant (AP) is a known inhibitor of cytochrome P450 3A4 which may affect tacrolimus metabolism. We retrospectively examined the effect of oral AP on intravenous tacrolimus concentrations in 26 patients undergoing reduced intensity transplantation from 09/2005 to 09/2006. Oral AP 125 mg daily was administered on transplant day +1 and 80 mg on days +2 and +3. Intravenous tacrolimus was administered as a 0.03 mg/kg/day continuous infusion on day -6 through day +1 (pre-AP), during-AP (days +2 to +7), and post-AP starting on day +8. Tacrolimus doses were adjusted to achieve concentrations of 5-20 ng/mL. Dose-corrected tacrolimus concentrations (ng/mL/mg per dose) in the pre-AP, during-AP, and post-AP time periods were: 8.12 (95% CI: 7.3-9.1), 11.63 (95% CI: 9.63-13.63), and 11.42 (95% CI: 8.12-14.7), respectively (P<0.01 between pre-AP and during-AP, P<0.01 between during-AP and post-AP, P = 0.01 between pre-AP and post-AP time periods). Although statistically significant, the observed rise was not clinically significant between during-AP and post-AP time periods. Previous work has shown that AP is not expected to exert an inhibitory effect within 48 h of AP discontinuation. Collectively, these data suggest that AP effect on tacrolimus metabolism is of minor clinical significance. A controlled trial is needed to confirm these findings.

Cross-reactivity between paclitaxel and hazelnut: a case report.

A 73-year-old Caucasian woman with metastatic bladder cancer developed hives, itching, difficulty in breathing, and general ill-feeling during the first 10 min of her first infusion of paclitaxel. Paclitaxel was discontinued and the symptoms resolved after intravenous diphenhydramine and hydrocortisone treatment. Upon discussion with the patient, she described the sensation as similar to her reaction to hazelnuts. The patient's only other allergy was to azithromycin, which presented as hives. A PubMed literature search revealed that paclitaxel is found in the components of the hazelnut tree and its nuts. While a nut-protein allergy cannot be ruled out, a cross-reaction between paclitaxel and hazelnuts is a possibility. Patients who describe an allergy to hazelnuts must be carefully observed while being treated with paclitaxel. The hazelnut allergy may not be a nut-protein allergy at all, but rather an allergy to the components of paclitaxel that reside in the hazelnut itself.

Thalidomide for the treatment of histiocytic sarcoma after hematopoietic stem cell transplant.

Histiocytic sarcoma (HS) is a rare neoplasm of uncertain etiology. Most recently, the diagnostic criteria for this entity have been revised with inclusion of diagnostic modalities such as immunohistochemical and cytogentic techniques. HS tends to have an aggressive clinical course and presents with systemic symptoms of fever, weight loss, adenopathy, hepatosplenomegly, rash, and pancytopenia. Thalidomide is a promising agent that may exert a therapeutic benefit in HS. We report a case of a 48-year-old female with HS who presented with fever, weight loss, fatigue, generalized anasarca, and pancytopenia. She underwent multi-agent chemotherapy followed by matched unrelated hematopoietic stem cell transplant. Her disease recurred and thalidomide therapy was started, with her overall disease burden significantly reduced as measured radiographically.

Palifermin in a hematopoietic stem cell transplant patient with osteonecrosis of the jaw.

This case report describes the use of palifermin in a multiple myeloma patient with a history of osteonecrosis of the jaw (ONJ) for the prevention of high-dose chemotherapy-induced mucositis. Following the day of autologous stem cell infusion, palifermin was discontinued secondary to adverse events. Specifically, palifermin-associated macroglossia seemed to exacerbate the pain localized in the oral cavity area affected by ONJ, necessitating escalated doses of narcotic analgesics. When contemplating palifermin as a mucosal protectant in a hematopoietic stem cell transplant patient with ONJ, a careful benefit-to-risk assessment is in order to ensure optimal effectiveness without undue harm.

The sulfone syndrome secondary to dapsone prophylaxis in a patient undergoing unrelated hematopoietic stem cell transplantation.

Dapsone is commonly used for pneumocystis carinii pneumonia (PCP) prophylaxis in immunocompromised patients. It has been used as an alternative therapy in the hematopoietic stem cell transplant (HSCT) setting in patients who can't tolerate trimethoprim-sulfamethoxazole. The Sulfone syndrome is not a well-known sequela of dapsone therapy and occurs at various doses, ranging from 50-300 mg/d. In all cases the syndrome occurs within 2 months of initiating therapy. Its clinical manifestations include: fever, methemoglobinemia, hemolytic anemia, exfoliative dermatitis and transaminits. A 51-year old female underwent a matched unrelated hematopoiectic stem cell transplant for acute mylogenous leukemia. Dapsone therapy was initiated on day +28 at a dose of 100 mg/day for PCP prophylaxis secondary to the patient's history of a sulfonamide allergy. On day +59, one month after initiation of therapy she developed hepatitis, hemolytic anemia, fever and methemoglobinemia of 8%. She was transferred to the intensive care unit and subsequently developed an exfoliative dermatitis. We conclude that the clinical presentation of this patient after HSCT on dapsone therapy coincide with the sulfone syndrome not previously described in a patients after HSCT.

Anti-thrombin III in the management of hematopoietic stem-cell transplantation-associated toxicity.

OBJECTIVE: To describe the evidence assessing the use of anti-thrombin III (AT-III) in the management of toxicity associated with hematopoietic stem-cell transplantation (HSCT)-conditioning regimens. DATA SOURCES: Clinical literature was accessed through conference proceedings, EMBASE, the Cochrane database, and MEDLINE (1966-December 2003). STUDY SELECTION AND DATA EXTRACTION: Case reports, small case series, case-control and cohort studies, and randomized controlled trials of AT-III in HSCT were evaluated. Publications examining AT-III use in the non-HSCT setting were also explored. Key search terms included AT-III, transplantation, and veno-occlusive disease (VOD). DATA SYNTHESIS: Severe VOD and ensuing multiple organ dysfunction is associated with high mortality in HSCT. A low AT-III level has been shown to correlate with the development of organ dysfunction. Phase II trials, case series, and one small, randomized, placebo-controlled study suggest a benefit when AT-III therapy is instituted early in the course of VOD/multiple organ dysfunction syndrome. In all of these reports, AT-III use was devoid of adverse events. CONCLUSIONS: Although further studies are needed to ascertain the optimal target level, method, and duration of administration, AT-III is still a viable alternative for the treatment of severe VOD and ensuing multiple organ dysfunction.