Urine mesna excretion after intravenous and oral dosing in ifosfamide-treated children

Purpose To describe mesna excretion in children.Patients and methods We studied 14 children (aged 1–18 years) who received 1.8 g/m² of ifosfamide per day for 5 days. For uroprotection, the children were given intravenous mesna (equal to 20% of the ifosfamide dose) followed by two oral doses (each equal to 40% of the ifosfamide dose). The concentrations of mesna and the metabolite dimesna were measured in urine samples collected on treatment days 1 and 5.Results Of 14 patients enrolled, 11 (aged 4–18 years) were evaluable. The profiles of mesna excretion rates were similar on days 1 and 5. Mesna excretion declined rapidly over 1–2 h after intravenous dosing. Increases in mesna excretion after oral dosing lagged by 2–4 h. About 21% of the mesna administered was excreted unchanged over 24 h on both days 1 and 5. The proportion excreted varied by severalfold between patients, but there was no association with age.Conclusion The profile of mesna excretion after intravenous and oral dosing in these children was similar to that in reported studies of ifosfamide-treated adults.     

Disposition of irinotecan and SN-38 following oral and intravenous irinotecan dosing in mice

The present study was conducted to quantitate the disposition of irinotecan lactone and its active metabolite SN-38 lactone in mice following oral and intravenous administration, and to evaluate the systemic exposure of irinotecan lactone and SN-38 lactone associated with antitumor doses of irinotecan lactone in mice bearing human tumor xenografts. Nontumor-bearing mice were given a single oral or intravenous irinotecan dose (5, 10, 40, or 75 mg/kg), and serial plasma samples were subsequently obtained. Irinotecan and SN-38 lactone plasma concentrations were measured using an isocratic HPLC assay with fluorescence detection. The disposition of intravenous irinotecan lactone was modeled using a two-compartment pharmacokinetic model, and the disposition of oral irinotecan and SN-38 lactone was modeled with noncompartmental methods. Irinotecan lactone showed biphasic plasma disposition following intravenous dosing with a terminal half-life ranging between 1.1 to 3 h. Irinotecan lactone disposition was linear at lower doses (5 and 10 mg/kg), but at 40 mg/kg irinotecan lactone clearance decreased and a nonlinear increase in irinotecan lactone AUC was observed. The steady-state volume of distribution ranged from 19.1 to 48.1 l/m². After oral dosing, peak irinotecan and SN-38 lactone concentrations occurred within 1 h, and the irinotecan lactone bioavailability was 0.12 at 10 mg/kg and 0.21 at 40 mg/kg. The percent unbound SN-38 lactone in murine plasma at 1000 ng/ml was 3.4 ± 0.67%, whereas at 100 ng/ml the percent unbound was 1.18 ± 0.14%. Irinotecan and SN-38 lactone AUCs in micebearing human neuroblastoma xenografts were greater than in nontumor-bearing animals. Systemic exposure to unbound SN-38 lactone in nontumor-bearing animals after a single oral irinotecan dose of 40, 10, and 5 mg/kg was 28.3, 8.6, and 2.9 ng h/ml, respectively. Data from the present study provide important information for the design of phase I studies of oral irinotecan. Received: 30 August 1996 / Accepted: 27 November 1996     

Busulfan pharmacokinetics following intravenous and oral dosing regimens in children receiving high-dose myeloablative chemotherapy for high-risk neuroblastoma as part of the HR-NBL-1/SIOPEN trial

IntroductionBusulfan is widely used in a neuroblastoma setting, with several studies reporting marked inter-patient variability in busulfan pharmacokinetics and pharmacodynamics. The current study reports on the pharmacokinetics of oral versus intravenous (IV) busulfan in high-risk neuroblastoma patients treated on the European HR-NBL-1/SIOPEN study.MethodsBusulfan was administered four times daily for 4 days to children aged 0.7–13.1 years, either orally (1.45–1.55 mg/kg) or by the IV route (0.8–1.2 mg/kg according to body weight strata). Blood samples were obtained prior to administration, 2, 4, and 6 h after the start of administration on dose 1. Busulfan analysis was carried out by gas chromatography–mass spectrometry and data analysed using a NONMEM population pharmacokinetic approach.ResultsBusulfan plasma concentrations obtained from 38 patients receiving IV busulfan and 25 patients receiving oral busulfan, were fitted simultaneously using a one-compartment pharmacokinetic model. Lower variability in drug exposure was observed following IV administration, with a mean busulfan area under the plasma concentration versus time curve (AUC) of 1146 ± 187 μM.min (range 838–1622), as compared to 953 ± 290 μM.min (range 434–1427) following oral busulfan. A total of 87% of children treated with IV busulfan achieved AUC values within the target of 900–1500 μM.min versus 56% of patients following oral busulfan. Busulfan AUC values were significantly higher in HR-NBL-1/SIOPEN trial patients who experienced hepatic toxicity or veno-occlusive disease (VOD) (1177 ± 189 μM.min versus 913 ± 256 μM.min; p = 0.0086). Further stratification based on route of administration suggested that the incidence of hepatic toxicity was related to both high busulfan AUC and oral drug administration.ConclusionThe reduced pharmacokinetic variability and improved control of busulfan AUC observed following IV administration support its utility within the ongoing HR-NBL-1/SIOPEN trial.     

Itraconazole trough concentrations in antifungal prophylaxis with six different dosing regimens using hydroxypropyl-beta-cyclodextrin oral solution or coated-pellet capsules

We have previously shown that a trough concentration of at least 500 ng ml-1 itraconazole is necessary for an effective antifungal prophylaxis in neutropenic patients. Since the bioavailability of itraconazole is reduced in these patients, a satisfactory dosing regimen remains to be defined. In this study, six dosing regimens with itraconazole capsules 400, 600 or 800 mg day-1, itraconazole solution 400 mg day-1 (additional loading dose: 400 mg day-1 solution for 2 days), 800 mg day-1 or 400 mg day-1 (additional loading dose: 800 mg day-1 capsules for 7 days, s/c1200) were compared during 160 courses of myelosuppressive chemotherapy in 123 patients with acute leukaemia. After the first week, patients taking 800 mg day-1 or 400 mg day-1 (s/c1200) itraconazole solution achieved significantly higher trough concentrations (high-performance liquid chromatography) than patients in other groups (P < 0.05) and 87 and 100%, respectively, of these had concentrations > 500 ng ml-1. Contrary to a dose of 400 mg day-1, a dose of 800 mg day-1 itraconazole solution induced severe nausea and vomiting in 46% of the patients. We conclude that 400 mg day-1 itraconazole solution with a loading dose of 800 mg day-1 capsules for 7 days resulted in sufficient trough concentrations from the first week onwards and appears to be suitable for antifungal prophylaxis in neutropenic patients.     

Management of the adverse effects associated with intravenous bisphosphonates.

Intravenous bisphosphonates are widely used to treat hypercalcemia and to reduce skeletal-related morbidity among cancer patients. However, serious complications, generally occurring in less than 2% of patients participated in phase III clinical trials, including acute systemic inflammatory reaction, ocular inflammation, renal failure, nephrotic syndrome, electrolyte imbalance, and osteonecrosis of the maxilla and mandible have all been increasingly reported. Yet, strategies to deal with these complications are becoming clear. Acute systemic inflammatory reaction is often self-limited and becomes less intense during subsequent treatments. For patients who develop ocular symptoms, prompt ophthalmologic evaluation is crucial to determine the safety of a subsequent bisphosphonate therapy. Patients who receive long-term pamidronate should be evaluated at intervals for early sign of nephritic syndrome as timely cessation of the agent may result in a full recovery. To reduce the risk of severe electrolyte abnormalities, particularly hypocalcemia, correcting any pre-treatment electrolyte abnormality and supplementing vitamin D and calcium may be helpful. Finally, to reduce the risk of osteonecrosis of the maxilla and mandible, obtaining a full dental evaluation before treatment and avoidance of invasive dental procedures is suggested. The three commonly used intravenous bisphosphonates (pamidronate, zoledronic acid, and ibandronate), are generally safe; ibandronate has to date been the least reported to be associated with renal side effects. As clinical indications of intravenous bisphosphonates continue to expand, prescribing clinicians should be familiar with these possible adverse effects and discuss them with patients before commencing or continuing on therapy.     

Exposure to oral bisphosphonates and risk of cancer

Recently, oral bisphosphonate use has increased markedly in the United States and elsewhere. Little is known about cancer risks associated with these drugs. A few studies have observed associations between bisphosphonates and the risk of breast, colorectal and esophageal cancer. However, the risk of all cancer and the risk of other cancers have not been investigated. In our study, we examined the risk of all cancer and site specific cancers in individuals taking bisphosphonates. Data were extracted from the UK General Practice Research Database to compare site-specific cancer incidence in a cohort of oral bisphosphonate users and a control cohort. Hazard ratios (HRs) were calculated using Cox regression modeling. The bisphosphonate and control cohort contained 41,826 participants (mean age 70, 81% female). Overall, the bisphosphonate cohort compared with the control cohort had a reduced risk of all cancer after any bisphosphonate usage [HR=0.87, 95% confidence interval (CI) 0.82, 0.92]. In the bisphosphonate cohort, compared with the control cohort, there was no evidence of a difference in the risk of lung (HR=1.03, 95% CI 0.88, 1.20) or prostate cancer (HR=0.86, 95% CI 0.67, 1.09) but breast (HR=0.71, 95% CI 0.62, 0.81) and colorectal cancer (HR=0.74, 95% CI, 0.60-0.91) were both reduced. Our findings indicate that bisphosphonates do not appear to increase cancer risk. Although reductions in breast and colorectal cancer incidence were observed in bisphosphonate users it is unclear, particularly for breast cancer, to what extent confounding by low bone density may explain the association.     

Efficacy and safety of intravenous bisphosphonates in patients with bone metastases caused by metastatic breast cancer

Solid tumors frequently metastasize to bone. This results in debilitating skeletal complications such as intractable bone pain, pathologic fractures, spinal cord compression, and hypercalcemia. Patients frequently require palliative radiation therapy or orthopedic surgery. Bisphosphonates have been shown to delay the incidence and decrease the frequency of skeletal-related events. Zoledronic acid is the only bisphosphonate that has provided benefits for patients with bone metastases secondary to a broad range of solid tumors. Among patients with metastatic breast or prostate cancer, zoledronic acid has demonstrated significant reductions in pain and skeletal morbidity compared with placebo. Zoledronic acid has also shown significant reductions in skeletal morbidity in patients with lung cancer or other solid tumors compared with placebo. Zoledronic acid is generally well tolerated. Flu-like symptoms which are manageable with standard treatment can occur. Renal monitoring is recommended, with dose reductions for patients with renal dysfunction. Osteonecrosis has been reported in patients receiving bisphosphonates and might be avoidable with appropriate dental care.     

Safety of long-term administration of bisphosphonates in elderly cancer patients

BACKGROUND: To evaluate the effectiveness and tolerability of the long-term treatment bone metastases with pamidronate in older patients. MATERIALS AND METHODS: Twenty-two ambulatory patients aged 70 or older were included in the study. The median age was 73 (range 70-77). Ten patients (46%) were affected by breast carcinoma, 7 (32%) by prostate carcinoma and 5 (22%) by multiple myeloma. Nine (40%) patients presented co-morbidity. All of the patients presented at least one metastatic lytic bone lesion measuring 1 cm or more in diameter; the median lesion number was 2 (range 1-4). Hormonal therapy or chemotherapy regimen, were allowed as clinically required. Patients were treated with a fixed dose of sodium pamidronate, 90 mg in 3 h infusion every 4 weeks. RESULTS: Partial response was shown in 6 (28%) patients, stable disease in 11 (50%), and progression (PD) in 5 (22%). 2 out of 5 patients with PD presented skeletal-related events (SREs) such as bone fracture. The median treatment duration was 19 months. The treatment was well tolerated; in 5 patients (23%) a GI fever was observed, in 3 patients (18%) G1 nausea, and in 3 patients (14) G1 diarrhea. Two cases (9%) of acute renal insufficiency (creatinine 1.7 and 1.6 mg/dl), and 3 cases (14%) of hypocalcemia (7.6, 7.5 and 7.8 mg/dl) were also registered. The renal dysfunction was reversible and without consequence. CONCLUSION: Our experience suggests that the bisphosphonates long-term administration is useful and did not cause significant side effects in elderly subjects. Low-grade pyrexia, nausea/vomiting, acute/reversible renal dysfunction and hypo-calcemia were the most frequent side effects reported. However, they were of low grade and in most cases, did not require dose modifications and/or hospitalization.     

Immunotoxicity of multiple dosing regimens of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes

We have shown that doxorubicin entrapped in cardiolipin liposomes retain antitumour efficacy in mice but had diminished cardiac uptake and cardiotoxicity. Such liposomes are preferentially taken up by spleen. In a previous study we showed that a single dose of liposomal doxorubicin is not more toxic than free doxorubicin with regard to immunologic parameters including generation of cytotoxicity for histocompatibility alloantigens and mitogenic responsiveness. In the present study, we have explored clinically relevant multiple dosing at weekly intervals, 2, 3, or 4 times. Again, despite splenic localization of liposomal doxorubicin, the depressive effect on these immunological parameters is not greater than the effect of free drug, and, in addition, the damage is repaired earlier.     

Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases

Background:

The presence of bone metastases in patients with metastatic renal cell carcinoma treated with oral tyrosine kinase inhibitors (TKIs) is associated with poorer outcome as compared with patients without bone involvement. Concomitant bisphosphonates could probably improve outcomes but also induce osteonecrosis of the jaw (ONJ).

Methods:

Retrospective study on all the renal cell carcinoma patients with bone metastases treated with sunitinib or sorafenib between November 2005 and June 2012 at the University Hospitals Leuven and AZ Groeninge in Kortrijk.

Results:

Seventy-six patients were included in the outcome analysis: 49 treated with concomitant bisphosphonates, 27 with TKI alone. Both groups were well balanced in terms of prognostic and predictive markers. Response rate (38% vs 16% partial responses, P=0.028), median progression-free survival (7.0 vs 4.0 months, P=0.0011) and median overall survival (17.0 vs 7.0 months, P=0.022) were significantly better in patients receiving bisphosphonates. The incidence of ONJ was 10% in patients treated with TKI and bisphosphonates.

Conclusion:

Concomitant use of bisphosphonates and TKI in renal cell carcinoma patients with bone involvement probably improves treatment efficacy, to be confirmed by prospective studies, but is associated with a high incidence of ONJ.     

Alternative temozolomide dosing regimens and novel combinations for the treatment of advanced metastatic melanoma

Over the past 30 years, there has been no significant improvement in treatment outcomes for patients with advanced stage IV metastatic melanoma, and prognosis remains poor. Melanoma is known to be responsive to immunomodulatory agents, to be a highly vascular tumor, and to be fairly resistant to standard cytotoxic chemotherapy. Ongoing research is attempting to find novel combinations that may have therapeutic synergy. Alternative dose-dense schedules of temozolomide appear promising and are being actively investigated, based on their potential to overcome chemoresistance to alkylating agents and the proven activity of temozolomide in the brain. Outcomes of studies investigating single-agent temozolomide suggest that it has activity similar to single-agent dacarbazine. Other studies combining temozolomide with either interferon-alfa or thalidomide suggest that the addition of these immunomodulatory agents to temozolomide improves response rates and may improve overall survival. The best results have been achieved with the extended, daily, dose-dense temozolomide regimen. Further research is needed to determine the optimal temozolomide regimen and best combination approach for the treatment of advanced metastatic melanoma.     

Safety and efficacy of bisphosphonates beyond 24 months in cancer patients.

PURPOSE: Bisphosphonate therapy has decreased the risk of skeletal complications associated with osteolytic bone lesions in patients with breast cancer and multiple myeloma. The large prospective studies have used 21 to 24 months of treatment. We studied the safety and efficacy of bisphosphonates in a subset of patients who received therapy for more than 24 months. PATIENTS AND METHODS: Patients who received bisphosphonates (pamidronate or zoledronic acid) were identified. Data on skeletal events and laboratory parameters were gathered by chart review. RESULTS: We studied 22 patients who received intravenous pamidronate or zoledronic acid for a duration of 3.6 years (range, 2.2 to 6.0 years). Prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were encountered. There was a clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine in these patients. The fracture rate beyond 2 years was no greater than during the first 2 years of treatment. There were no stress fractures of long bones with prolonged therapy. CONCLUSION: Prolonged treatment with the potent bisphosphonates pamidronate and zoledronic acid seems to be well tolerated and should be studied in prospective, randomized studies to document prolonged skeletal efficacy.     

Pharmacokinetics of once and twice daily dosing of intravenous tobramycin in paediatric patients with cystic fibrosis

The optimal dosing of intravenous tobramycin for treatment of pulmonary exacerbations in paediatric cystic fibrosis (CF) patients has not been completely delineated. We performed a retrospective study evaluating the pharmacokinetics and pharmacodynamics of once daily dosing (ODD) of IV tobramycin compared to twice daily dosing (TDD). Fifty-nine and 44 patients were included in the ODD and TDD groups, respectively. Once daily dosing achieved higher C_max as compared to TDD (29.5?±?11.0 vs 19.0?±?4.9, P?P?P?C_max:MIC for MICs >1.0?mg/l. Twice daily dosing may be a viable alternative to ODD in treating organisms with MICs ≤?1.0?mg/l; however, with MICs >1.0?mg/l, ODD is likely necessary to achieve goal C_max:MIC ratios.     

Osteonecrosis of the jaws in patients with bone metastasis receiving intravenous bisphosphonates. A rising concern

Osteonecrosis of the jaws (ONJ) is a recognized complication of bisphosphonates (BP) therapy in cancer patients with bone metastasis. We report 2 additional cases of ONJ in women with breast cancer after long-term exposure to BP, discussing some considerations about the presentation and management of this rare and new complication.     

Combined intravenous and oral mesna in outpatients treated with ifosfamide

Purpose: To prevent hemorrhagic cystitis, mesna is typically injected intravenously (IV) at the time of an ifosfamide dose and 4 and 8 h later. To simplify outpatient ifosfamide therapy, we gave the second and third mesna doses orally. Methods: The mesna doses (400 or 600 mg/m²) were 40% (w/w) of each ifosfamide dose (1.0 or 1.5 g/m²), which was given daily for 5 days. We evaluated urinary mesna excretion and plasma concentrations in ten patients from the beginning of mesna infusion until the time of the second oral dose. The first oral dose was administered at hour 2 in the last six patients to allow time for absorption of mesna. Results: The rate and amount of mesna excretion was less variable over time and among patients after oral than after IV administration. No macrohematuria was observed in these ten patients nor in an additional 50 patients given oral mesna at hours 2 and 8 during at least two cycles of ifosfamide therapy. Conclusion: These pharmacokinetic and clinical efficacy data support the use of a combined regimen of IV and oral mesna to simplify outpatient ifosfamide administration. Received: 16 July 1996 / Accepted: 17 December 1996