[Show abstract][Hide abstract] ABSTRACT: PURPOSE: It is advantageous to individualize high-dose methotrexate (HDMTX) to maintain adequate exposure while minimizing toxicities. Previously, we accomplished this through within-course dose adjustments. METHODS: In this study, we evaluated a strategy to individualize HDMTX based on clearance of each individual's previous course of HDMTX in 485 patients with newly diagnosed acute lymphoblastic leukemia. Doses were individualized to achieve a steady-state plasma concentration (Cpss) of 33 or 65 μM (approximately 2.5 or 5 g/m(2)/day) for low- and standard-/high-risk patients, respectively. RESULTS: Individualized doses resulted in 70 and 63 % of courses being within 20 % of the targeted Cpss in the low- and standard-/high-risk arms, respectively, compared to 60 % (p < 0.001) and 61 % (p = 0.43) with conventionally dosed therapy. Only 1.3 % of the individualized courses in the standard-/high-risk arm had a Cpss greater than 50 % above the target compared to 7.3 % (p < 0.001) in conventionally dosed therapy. We observed a low rate (8.5 % of courses) of grade 3-4 toxicities. The odds of gastrointestinal toxicity were related to methotrexate plasma concentrations in both the low (p = 0.021)- and standard-/high-risk groups (p = 0.003). CONCLUSIONS: Individualizing HDMTX based on the clearance from the prior course resulted in fewer extreme Cpss values and less delayed excretion compared to conventional dosing.
Cancer Chemotherapy and Pharmacology 06/2013; · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:Limited information exists regarding the use of posaconazole for treating systemic fungal infections in children, adolescents, and young adults with cancer. At St. Jude Children's Research Hospital, the recommended posaconazole dose in patients weighing less than 34 kg is 18-24 mg/kg daily, given in 4 divided doses. For patients aged 13 years or older or those weighing 34 kg or more, the recommended dose is 800 mg daily, given orally in 4 divided doses.OBJECTIVE:To determine whether the current posaconazole dosing guidelines achieve target posaconazole plasma concentrations of 0.7 μg/mL or greater.METHODS:This retrospective clinical study examined data from patients who received treatment-dose posaconazole and had at least 1 posaconazole plasma concentration measurement.RESULTS:Data from 33 patients who received posaconazole for the treatment of fungal infections were analyzed. The median age of patients was 11.5 years (range 0.5-23.2). Twenty-one of 33 patients (63.6%) had posaconazole concentrations of 0.7 μg/mL or greater (median 1.4; range 0.7-2.98) at the first measurement. The median posaconazole dosage referenced to total body weight in these patients was 20 mg/kg/day. Patients with concentrations less than 0.7 μg/mL (median 0.4; range 0.025-0.69) received lower posaconazole dosages when referenced to body weight (median 12.9 mg/kg/day; p = 0.02). Of the 12 patients with concentrations less than 0.7 μg/mL, 7 (58.3%) were aged 13 years or older.CONCLUSIONS:The current dosing approach for posaconazole yielded therapeutic plasma concentrations more frequently in patients younger than 13 years than in those 13 years or older. This difference may be related to the practice of capping adolescent and young adult doses at the suggested maximum adult daily dose. Therefore, we recommend weight-based dosing in all pediatric, adolescent, and young adult patients with cancer, with routine therapeutic drug monitoring to ensure adequate concentrations.
Annals of Pharmacotherapy 06/2013; · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: High-dose methotrexate (HDMTX)-induced acute kidney injury is a rare but life-threatening complication. The methotrexate rescue agent glucarpidase rapidly hydrolyzes methotrexate to inactive metabolites. The authors retrospectively reviewed glucarpidase use in pediatric cancer patients at their institution and evaluated whether subsequent resumption of HDMTX was tolerated.
Clinical data and outcomes of all patients who received glucarpidase after HDMTX administration were reviewed.
Of 1141 patients who received 4909 courses of HDMTX, 20 patients (1.8% of patients, 0.4% of courses) received 22 doses of glucarpidase. The median glucarpidase dose was 51.6 U/kg (range, 13-65.6 U/kg). At the time of administration, the median plasma methotrexate concentration was 29.1 μM (range, 1.3-590.6 μM). Thirteen of the 20 patients received a total of 39 courses of HDMTX therapy after glucarpidase. The median time to complete methotrexate excretion was 355 hours (range, 244-763 hours) for the HDMTX course during which glucarpidase was administered, 90 hours (range, 66-268 hours) for the next HDMTX course, and 72 hours (range, 42-116 hours) for subsequent courses. The median peak serum creatinine level during these HDMTX courses was 2.2 mg/dL (range, 0.8-9.6 mg/dL), 0.8 mg/dL (range, 0.4-1.6 mg/dL), and 0.6 mg/dL (range, 0.4-0.9 mg/dL), respectively. One patient experienced nephrotoxicity upon rechallenge with HDMTX. Renal function eventually returned to baseline in all patients, and no patient died as a result of methotrexate toxicity.
The current results indicated that it is possible to safely resume HDMTX therapy after glucarpidase treatment for HDMTX-induced acute kidney injury.
Cancer 01/2012; 118(17):4321-30. · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Improved cure rates for childhood acute lymphoblastic leukemia (ALL) over the past 2 decades have allowed greater attention to patients' quality of life. Neuropathic pain (NP) is an unpleasant side effect of chemotherapeutic agents for leukemia, especially vincristine.
We retrospectively reviewed the records of 498 patients treated on a single protocol for ALL to investigate the risk factors, the incidence, and the use of therapeutic and prophylactic gabapentin treatment for NP.
White non-Hispanic race was the only patient variable predictive of NP. One hundred and seventy-four of 498 patients (34.9%) experienced 207 episodes of NP; 16% (28 of 174) patients experienced at least one recurrence of pain after the initial episode. No statistical significance was found in the relation between the severity (grade) of the NP episode and the cumulative dose of vincristine (P = 0.45) or the vincristine dose that immediately preceded the diagnosis (1.5 mg/m(2) versus 2.0 mg/m(2) [correction made here after initial online publication], P = 0.59). Of 180 episodes with treatment data, 62.2% (112) and 37.8% (68) were treated with gabapentin or opioids, respectively. The selection of treatment with gabapentin or opioids was not influenced by the pain intensity score at the time of diagnosis of NP (P = 0.91). The mean gabapentin dose used for 112 episodes was 15.5 mg/kg/day (SD 7.9). We found no evidence that gabapentin prevented recurrence of NP.
Our results highlight the need for prospective randomized studies to elucidate the value of gabapentin regimen for prevention or treatment of vincristine-related pain during treatment of childhood leukemia.
Pediatric Blood & Cancer 02/2011; 57(7):1147-53. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Allopurinol and urate oxidase are both effective in preventing or treating hyperuricemia during remission induction therapy for lymphoid malignancies, but to the authors' knowledge, their effects on concomitant anticancer drug therapy have not been compared.
The authors compared plasma methotrexate pharmacokinetics in pediatric patients with newly diagnosed acute lymphoblastic leukemia who received concomitant allopurinol (n = 20) versus those treated with nonrecombinant or recombinant urate oxidase (n = 96) during high-dose methotrexate administration before conventional remission induction therapy.
The minimum plasma concentration of uric acid was significantly (P < .0001) lower after urate oxidase treatment than the concentration after allopurinol treatment. Methotrexate clearance was significantly higher (median, 117.1 mL/minute/m(2) vs 91.1 mL/minute/m(2); P = .019) in patients who received urate oxidase. A higher proportion of patients in the allopurinol group had elevated methotrexate plasma concentrations (36% vs 7%; P = .003) and experienced mucositis (45% vs 16%; P = .003) after methotrexate treatment compared with the urate oxidase group.
The lower rate of methotrexate clearance in patients who received allopurinol likely reflected a less potent hypouricemic effect of allopurinol, leading to precipitation of uric acid in renal tubules. Hence, during remission induction therapy for lymphoid malignancies, the authors concluded that renally excreted drugs should be monitored closely, especially in patients who are receiving allopurinol.
Cancer 10/2009; 116(1):227-32. · 4.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Systemic and intrathecal methotrexate (MTX) are integral components of acute lymphoblastic leukemia (ALL) therapy, but can be associated with neurotoxicity. We describe here the case of an adolescent male with T-cell ALL who developed recurrent episodes of subacute neurotoxicity characterized by slurred speech, emotional lability, and hemiparesis after intrathecal MTX administration. Serial magnetic resonance imaging with diffusion-weighted imaging showed recurrent areas of restricted diffusion within cerebral hemispheric white matter, which correlated chronologically with the administration of intrathecal therapy and severity of clinical symptoms. Resolution of diffusion abnormalities did not preclude further toxicity and a large lesion could cause persisting symptoms.
Pediatric Blood & Cancer 11/2008; 52(2):293-5. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Therapeutic drug monitoring (TDM) may be useful to optimize voriconazole therapy, but no consensus exists regarding the therapeutic range. Data on voriconazole pharmacokinetics and TDM in children is limited. We evaluated the pharmacokinetics of voriconazole in pediatric cancer patients and explored the potential application of voriconazole TDM.
Plasma voriconazole levels, patient demographics, indication, and other data were retrospectively collected from patients who received voriconazole between June 2004 and November 2007. Pharmacokinetic parameters, including clearance and area under the curve (AUC), were calculated for patients with three data points available (trough, peak, and 6-hr postdose).
Plasma voriconazole levels (60 trough, 29 peak, 11 random, and 29 6-hr postdose samples; total 129) from 48 patients (3 months to 20 years) receiving voriconazole as either prophylaxis (n=29) or treatment (n=19) were evaluated. The median (range) trough level was 0.25 (<0.2-10.00) µg/mL. Median dosage was higher in patients receiving voriconazole for treatment of an infection (4.3 mg/kg, 1.6-13 mg/kg) vs. those receiving prophylaxis (3.8 mg/kg, 2.2-5.7 mg/kg; p=0.014). However, median trough level did not differ in treatment group (<0.2, <0.2-8.4 µg/mL) vs. prophylaxis group (0.40, <0.2-10.00 µg/mL; p=0.19). When trough levels were stratified by age, the median trough level in patients less than 6 years old (<0.2 µg/mL, <0.2-10.00 µg/mL; n=34), was lower than that in older patients (0.62 µg/mL, <0.2-8.4 n=26; p=<0.001). For patients receiving IV voriconazole in whom PK parameters were calculated (n=6), the median clearance was 0.18 L/hr/kg and the AUC(0,12) was 25.54 mg*hr/L, which is comparable to published values.
Voriconazole trough levels were frequently undetectable in this cohort of patients. Patients less than 6 years old demonstrated lower median trough levels and may require more frequent dosing of voriconazole. TDM may have a role in optimizing voriconazole therapy, particularly for patients less than 6 years old.
2008 American College of Clinical Pharmacy Annual Meeting; 10/2008
[Show abstract][Hide abstract] ABSTRACT: Pleural effusions, ascites, and renal dysfunction decrease the plasma excretion of methotrexate (MTX). However, it is not known what effect these complications have on MTX clearance when they arise after the plasma MTX concentration has fallen to an undetectable level. We describe the clinical course and pharmacokinetics of MTX in a patient with acute lymphoblastic leukemia who experienced pleural effusions, ascites, and renal failure during the weeks after treatment with high-dose MTX (1.63 g/m2 i.v. over 24 h). The patient's normal initial MTX clearance rate (107 ml/min/m2) was consistent with his undetectable plasma level of MTX on day 9 after the infusion. His plasma MTX concentration then gradually increased as his renal function declined, reaching a peak of 0.72 microM on day 15. This unusual finding of an undetectable plasma MTX concentration that subsequently rose to persistent, potentially toxic levels was explained only by a pharmacokinetic model that accounted both for a third space at the time of treatment and for the subsequent decrease in the systemic elimination rate. Therefore, the finding of a physiologic third space during MTX administration combined with the detection of renal dysfunction in the following weeks should be an indication for prolonged therapeutic drug monitoring.
Cancer Chemotherapy and Pharmacology 09/2004; 54(2):146-52. · 2.57 Impact Factor