Rami B. Ibrahim

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.

Effect of buprenorphine on CYP3A activity in rat and human liver microsomes

Buprenorphine is a partial opioid agonist available in France as an alternative to methadone in the treatment of opiate-dependent individuals. Twenty deaths have been reported in patients who have ingested buprenorphine in combination with benzodiazepines. Since buprenorphine and many benzodiazepines are CYP3A substrates, the effect of buprenorphine on CYP3A activity was examined in order to assess the likelihood of a pharmacokinetic interaction. The formation of 6beta-hydroxytestosterone was measured in dexamethasone-induced rat liver microsomes and in human liver microsomes under control conditions and in the presence of buprenorphine. Buprenorphine was found to be a weak inhibitor of CYP3A with a 50% decrease in enzyme activity occurring at a concentration of 118 microM (IC50) in human liver microsomes. IC50 was 0.3 microM for ketoconazole in the same system. Since the IC50 for buprenorphine is roughly 2000 times higher than typical plasma concentrations, this drug is unlikely to cause clinically significant inhibition of CYP3A in patients. Excessive CNS depression due to the combination of buprenorphine and benzodiazepines is most likely due to additive or synergistic pharmacologic effect unrelated to a pharmacokinetic interaction between the drugs.

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 patients 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.

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.

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.

Safety of low-dose low-molecular-weight-heparins in thrombocytopenic stem cell transplantation patients: A case series and review of the literature

Summary:Few attempts have been made to examine the feasibility of safely administering low-molecular-weight-heparins (LMWHs) in the presence of concurrent thrombocytopenia. We retrospectively investigated the safety of low-dose LMWH in BMT patients, a population at risk of bleeding. In total, 26 patients received at least one dose of low-dose enoxaparin (ie <1 mg/kg/day) during thrombocytopenia. s.c. enoxaparin 40 mg once daily was given in 85% of the cohort. The mean number of platelet days <55 × 109 and <20 × 109/l were 16.5 days (95% CI=8.04–24.96) and 4.14 days (95% CI=2.35–5.93), respectively. The mean number of low-dose enoxaparin administration days when platelet <55 × 109 and 20 × 109/l were 9.89 days (95% CI=3.26–16.53) and 2.25 days (95% CI=0.57–3.93), respectively. Minor bleeding occurred in four patients (15%) whereas major episodes developed in two patients (8%). The latter two events occurred during the transition between full therapeutic (ie 1.5–2 mg/kg/day) and low-dose enoxaparin close to the onset of thrombocytopenia. The present case series, along with the discussed literature, descriptively suggests that low-dose enoxaparin may be safely administered at a platelet count in the range of 20 and 55 × 109/l in BMT patients who weigh >55 kg.

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.

Rhodococcus equi lung infection in an allogeneic hematopoietic stem cell transplant recipient

Abstract: In this report, we describe a case of Rhodococcus equi lung infection diagnosed in an allogeneic hematopoietic stem cell transplant with oral graft‐versus‐host disease 3 months after stem cell infusion. The lung lesion persisted despite an approximate 3 months of vancomycin therapy, but then responded favorably to a combination of intravenous ertapenem at 1 g daily and oral rifampin at 600 mg daily for 1 month. An overview of Rhodococcus infection in transplant recipients is presented. This case and the discussed literature suggest that combination antibiotic therapy is warranted in patients with decreased humoral and cellular immunity.

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, r2 = 0.92; p<0.05). The above results suggest that, under the studied conditions, cefepime removal by PE is clinically insignificant (∼4% of total 2 g dose).

Mandatory pharmacy residencies: One way to reduce medication errors.

We read with disbelief about a newly graduated pharmacist dispensing 30 times the amount of injectable sodium bicarbonate intended, an error that led to a patient’s death.[1][1] As clinicians, we wondered what clinical scenario might mandate the large amount of sodium bicarbonate dispensed—the