Pharmacokinetic variability of voriconazole and N-oxide voriconazole measured as therapeutic drug monitoring.

Voriconazole (VRC), a triazole agent is extensively metabolized by CYP2C19, CYP2C9, and to a lesser extent, by CYP3A4. Few data are available regarding disposition of the main VRC metabolite (MVRC; UK121,265). The aim of this study was to investigate the pharmacokinetic variability of VRC and MVRC plasma concentrations on the basis of 115 drug monitoring samples from patients treated with VRC. Plasma concentrations of VRC and MVRC were determined by HPLC assay. During the study period, therapeutic drug monitoring (TDM) of 39 adult in- and out-patients were realized. The residual interquartile range (IQR) were 0.5-2.6 mg/l (median: 1.4 mg/l) for VRC plasma concentrations and 1.6-3.4 mg/l for MVRC (median: 2.5 mg/l). Median IQR metabolic ratio [VRC]/[MVRC] was 0.2-1.1 (median: 0.6 mg/l). VRC C(min) was <1 mg/l in 41% of cases and <0.5 mg/l in 25% of them. Patients with VRC C(min) <1 mg/l have a lower [VRC]/[MVRC] ratio than patients with VRC C(min) ≥1 mg/l (median ratio 0.1 vs. 1.0 p < 0.0001). VRC TDM is now recommended to optimize their benefit/risk ratio. In addition, measurement of MVRC in unstable patients could quickly detect patients with impaired metabolism, in cases of subtherapeutic (C(min) <1 mg/l) or toxic (C(min) >5 mg/l) VRC plasma levels.

Posaconazole-increased vincristine neurotoxicity in a child: a case report.

A 9-year-old girl was managed according to the COPRALL 04 protocol for treatment of a relapse of acute lymphoblastic leukemia. Owing to a previous case of disseminated fusariosis, posaconazole was started 5 days before initiation of chemotherapy. Six days after the last dose of vincristine, the child reported symptoms of severe peripheral neuropathy, abdominal cramps, and constipation. After this, she developed fluctuations in her level of consciousness and seizures. After cessation of therapy with posaconazole, a complete resolution of the above occurred within 7 days. This case illustrates the possibility of vincristine toxicity exacerbated by coadministration of posaconazole. As posaconazole is an inhibitor of the isoenzyme CYP3A4, interactions with drugs that are metabolized via this pathway, such as vincristine, can be anticipated. Another possibility is that, like itraconazole, posaconazole may also inhibit P-glycoprotein-mediated vincristine efflux. Although case reports of neurotoxicity owing to possible interaction between itraconazole and vincristine exist in the literature, only 1 case report relating to the possible interaction between posaconazole and vincristine exists. Clinicians should be made aware of this possible drug-drug interaction.

Adverse effects of voriconazole: analysis of the French Pharmacovigilance Database.

BACKGROUND: The most common adverse effects of voriconazole reported during clinical trials were disturbances of vision (30% of pts.), skin rashes (17.3%), and elevations in hepatic enzymes level (approximately 10% of pts.; varying with enzymes). However, postmarketing data concerning safety of voriconazole are limited. OBJECTIVE: To describe voriconazole adverse drug effects (ADEs) after 4 years of the drug's availability in France and determine their occurrence. METHODS: All cases of ADEs including voriconazole reported to the French Pharmacovigilance Database between 2002 and 2005 were analyzed. For each case, the following data were recorded: age, sex, indication, concomitant disease, concomitant medications, and ADE description. Causality link between voriconazole and ADEs was performed using the Naranjo probability scale. RESULTS: A total of 227 ADE cases were reported in 178 adults and 9 children (<12 y), with 66% occurring in males. The patients' median age was 49.6 (2-80) years. ADEs included liver function test abnormalities (23%), visual disturbances (18%), skin rashes (17%), neurologic disturbances (14%), cardiovascular events (10%), hematologic disorders (8%), and renal disturbances (4%). Other less commonly identified ADEs included headache, nausea, vomiting, and diarrhea. Drug-drug interactions were observed in 7 cases. According to the Naranjo criteria, 84% of ADEs were classified as possible, 7% as probable, 5% as highly probable, and 4% as doubtful. CONCLUSIONS: Most ADEs found in this study are well documented in the literature, except for cardiac complications, which are rarely reported. Few ADEs related to drug interactions were observed; however, due to the extensive metabolism of voriconazole by cytochrome P450 isoenzymes, clinicians should be aware of potential interactions between voriconazole and other drugs metabolized through this pathway.

Neurotoxicity related to valganciclovir in a child with impaired renal function: usefulness of therapeutic drug monitoring.

OBJECTIVE: To report a case of neurotoxicity related to antiviral drugs, discuss the involvement of concomitant medications, and document the pharmacokinetics of ganciclovir (administered as valganciclovir) in a child with impaired renal function. CASE SUMMARY: A 13-year-old boy with acute lymphoblastic leukemia was treated for cytomegalovirus retinitis with valganciclovir 450 mg every 2 days in the course of hematopoietic stem cell transplantation. Concomitant medication included omeprazole, furosemide, and acetaminophen. During treatment, when creatinine clearance decreased to 20 mL/min, the child presented with acute neurotoxicity, consisting of mental confusion and hallucinations, which resolved when all medications were stopped. Valganciclovir therapeutic monitoring showed high ganciclovir concentrations in the plasma (3.85 microg/mL) and cerebrospinal fluid (2.6 microg/mL) 48 hours after the last valganciclovir dose. After recovery of neurologic function, valganciclovir was resumed at a lower dosage (225 mg twice a week) with therapeutic drug monitoring and was well tolerated. However, the cytomegalovirus infection was not resolved. The leukemia relapsed, and the patient had terminal renal failure and died. The Naranjo probability scale indicated a probable relationship between valganciclovir and neurotoxicity. DISCUSSION: Drugs taken by this child (acyclovir, valganciclovir, omeprazole) have been reported to induce neurotoxicity, with the pharmacokinetics of the first 2 being altered by renal failure. At the time when acyclovir was first administered, symptoms of neurotoxicity were already apparent. Moreover, plasma concentrations of ganciclovir were very high during the course of the neurotoxicity. Thus, the adverse effects seemed related to an overdosage of valganciclovir and were worsened by the addition of acyclovir. CONCLUSIONS: This case is informative because few clinical and pharmacokinetic data are available concerning the use of valganciclovir in children. A study should be performed to determine the proper pediatric dose of valganciclovir with and without renal impairment to prevent the occurrence of adverse effects.

Liquid chromatography-electrospray mass spectrometry determination of carbamazepine, oxcarbazepine and eight of their metabolites in human plasma.

Carbamazepine (CBZ) and oxcarbazepine (OXCBZ) are both antiepileptic drugs, which are prescribed as first-line drugs for the treatment of partial and generalized tonic-clonic epileptic seizures. In this paper, a specific and sensitive liquid chromatography-electrospray ionization mass spectrometry method was described for the simultaneous determination of carbamazepine (CBZ), oxcarbazepine (OXCBZ) and eight of their metabolites [CBZ-10,11-epoxide (CBZ-EP), 10,11-dihydro-10,11-trans-dihydroxy-carbamazepine (DiOH-CBZ), 10-hydroxy-10,11-dihydroCBZ (10-OH-CBZ), 2-hydroxycarbamazepine (2-OH-CBZ), 3-hydroxycarbamazepine (3-OH-CBZ), iminostilbene (IM), acridone (AO) and acridine (AI)] in human plasma. The work-up procedure involved a simple precipitation with acetone. Separation of the analytes was achieved within 50 min using a Zorbax eclipse XD8 C8 analytical column. The mobile phase consisted of a mixture of acetonitrile-formate buffer (2 mM, pH 3). Detection was performed using a quadrupole mass spectrometer fitted with an electrospray ion source. Mass spectrometric data were acquired in single ion recording mode at m/z 237 for CBZ, m/z 180 for CBZ-EP and AI, m/z 236 for OXCBZ, m/z 237 for 10-OH-CBZ, m/z 253 for 2-OH-CBZ, 3-OH-CBZ and DiOH-CBZ, m/z 196 for AO and m/z 194 for IM. For all analytes, the drug/internal standard peak height ratios were linked via a quadratic relationship to plasma concentrations. The extraction recovery averaged 90% for CBZ, 80% for OXCBZ and was 80-105% for the metabolites. The lower limit of quantitation was 0.5mg/l for CBZ, 0.4 mg/l for OXCBZ and ranged from 0.02 to 0.3 mg/l for the metabolites. Precision ranged from 2 to 13% and accuracy was between 86 and 112%. This method was found suitable for the analysis of plasma samples collected during therapeutic drug monitoring of patients treated with CBZ or OXCBZ.

Optimal management of methotrexate intoxication in a child with osteosarcoma.

OBJECTIVE: To describe the time course and management of methotrexate (MTX) toxicity in a 14-year-old Hispanic boy with osteosarcoma treated with high-dose MTX. CASE SUMMARY: During the sixth cycle of high-dose MTX, severe intoxication was observed with high MTX plasma concentrations, acute renal failure, and hepatitis, followed by mucositis and moderate myelosuppression. Intensification of urine alkalinization and increased leucovorin dosages did not decrease plasma concentrations of MTX or prevent systemic toxicities. Carboxypeptidase G2 and aminophylline were thus administered as a second-intention rescue strategy. Within 2 weeks, a recovery of clinical symptoms and normalization of the biological abnormalities were observed. Limb salvage surgery was performed, which permitted classifying the patient as an MTX high-responder. Thereafter, MTX was successfully resumed, leading to clinical recovery of the patient. Concomitantly, homocysteine plasma levels, a marker of the pharmacodynamic effect of MTX, were measured. During the intoxication, homocysteine plasma levels were significantly increased, parallel to the excessive MTX plasma concentrations observed. DISCUSSION: According to the excessive MTX levels measured in this patient, along with the observed clinical (mucositis) and biological (hepatitis, renal injury) adverse effects, we suggest that MTX may be a cause of these complications. Use of the Naranjo probability scale indicated a probable relationship between the complications and MTX. CONCLUSIONS: This observation shows that severe complications observed during one cycle of high-dose MTX is not predictive of the tolerability of further courses. Optimal management of such complications, using specific therapeutic intervention, may be considered.