BACKGROUND: This analysis was initiated to define the predictive value of the area under the curve of high-dose methotrexate (AUC HD-MTX ) in patients with primary central nervous system lymphoma (PCNSL). PATIENTS AND METHODS: We included 55 patients with PCNSL and available pharmacokinetic (PK) data from the International Extranodal Lymphoma Study Group (IELSG) no. 20 trial, randomised to HD-MTX (n ¼ 30) or HD-MTX and high-dose cytarabine (HD-AraC) (n ¼ 25). Individual AUC HD-MTX from population PK analysis was tested on drug toxicity and clinical outcome using multivariate logistic regression analysis and Cox hazards modelling. RESULTS: AUC HD-MTX , the IELSG score and treatment group were significant predictors for treatment response (complete or partial) in the adjusted model. The AUC HD-MTX did not predict toxicity, with the exception of liver toxicity and neutropaenia. A high AUC HD-MTX was associated with better event-free survival (EFS) (P ¼ 0.01) and overall survival (OAS) (P ¼ 0.02). Both the AUC HD-MTX and the IELSG score were significant predictors of EFS and OAS in the adjusted model, with a hazard ratio of 0.82 and 0.73, respectively, per 100 mmol l À1 h À1 increase in AUC HD-MTX .

Background and purpose: Lopinavir is extensively metabolized by cytochrome P450 3A (CYP3A) and is considered to be a substrate for the drug transporters ABCB1 (P-glycoprotein) and ABCC2 (MRP2). Here, we have assessed the individual and combined effects of CYP3A, ABCB1 and ABCC2 on the pharmacokinetics of lopinavir and the relative importance of intestinal and hepatic metabolism. We also evaluated whether ritonavir increases lopinavir oral bioavailability by inhibition of CYP3A, ABCB1 and/or ABCC2. Experimental approach: Lopinavir transport was measured in Madin-Darby canine kidney cells expressing ABCB1 or ABCC2. Oral lopinavir kinetics (+/-ritonavir) was studied in mice with genetic deletions of Cyp3a, Abcb1a/b and/or Abcc2, or in transgenic mice expressing human CYP3A4 exclusively in the liver and/or intestine. Key results: Lopinavir was transported by ABCB1 but not by ABCC2 in vitro. Lopinavir area under the plasma concentration -time curve (AUC)oral was increased in Abcb1a/b -/-mice (approximately ninefold vs. wild-type) but not in Abcc2 -/-mice. Increased lopinavir AUCoral (>2000-fold) was observed in cytochrome P450 3A knockout (Cyp3a -/-and Cyp3a/Abcb1a/b/Abcc2 -/-mice was observed. CYP3A4 activity in intestine or liver, separately, reduced lopinavir AUCoral (>100-fold), compared with Cyp3a -/-mice. Ritonavir markedly increased lopinavir AUCoral in all CYP3A-containing mouse strains. Conclusions and implications: CYP3A was the major determinant of lopinavir pharmacokinetics, far more than Abcb1a/b. Both intestinal and hepatic CYP3A activity contributed importantly to low oral bioavailability of lopinavir. Ritonavir increased lopinavir bioavailability primarily by inhibiting CYP3A. Effects of Abcb1a/b were only detectable in the presence of CYP3A, suggesting saturation of Abcb1a/b in the absence of CYP3A activity.

Methotrexate (MTX) at a dose of ≥1 g/m(2) remains the most efficient treatment against primary central nervous system lymphoma (PCNSL), and is the most widely used drug in prospective clinical trials. MTX is a folate analog that inhibits dihydrofolate reductase, thereby blocking de novo purine synthesis. MTX as well as 7-hydroxy-MTX, its main metabolite in serum, are both eliminated by the kidneys. The elimination of MTX is prolonged in patients with renal impairment and third-space fluid collections, and in patients receiving concurrent non-steroidal antirheumatic drugs, benzimidazoles and sulfonamides, among others. Main adverse events with high-dose MTX include severe myelosuppression, renal dysfunction and stomatitis. Supportive measures such as rigorous hydration, urine alkalinization and careful drug monitoring with supplemental leucovorin rescue are crucial to avoid significant toxicity. Strategies to optimize clinical efficacy of high-dose MTX in patients with PCNSL include administration of 3 h instead of longer infusions, potentially supplemented with an additional intravenous MTX bolus, and maintaining MTX dose intensity over the course of four treatment cycles. Some pharmacological studies suggest that achieving an MTX area under the plasma concentration-time curve (AUC(MTX)) of between 1000 and 1100 μmol.h/L may improve clinical outcome, but clinical data are not conclusive at present. In this review, we analyze the impact of patient, lymphoma and pharmacokinetic variables on the antitumor activity of high-dose MTX in patients with PCNSL, summarize recommendations for daily clinical practice and give some suggestions for future trials.

ABSTRACT:Atazanavir is a commonly prescribed protease inhibitor for treatment of HIV-1 infection. Thus far, only limited data are available on the in vivo metabolism of the drug. Three systemic circulating metabolites have been reported, but their chemical structures have not been released publicly. Atazanavir metabolites may contribute to its effectiveness but also to its toxicity and interactions. Thus, there is a need for extensive metabolic profiling of atazanavir. Our goals were to screen and identify previously unknown atazanavir metabolites and to develop a sensitive metabolite profiling method in plasma. Five atazanavir metabolites were detected and identified in patient samples using liquid chromatography coupled to linear ion trap mass spectrometry: one N-dealkylation product (M1), two metabolites resulting from carbamate hydrolysis (M2 and M3), a hydroxylated product (M4), and a keto-metabolite (M5). For sensitive semiquantitative analysis of the metabolites in plasma, the method was transferred to liquid chromatography coupled to triple quadrupole mass spectrometry. In 12 patient samples, all the metabolites could be detected, and possible other potential atazanavir keto-metabolites were found. Atazanavir metabolite levels were positively correlated with atazanavir levels, but interindividual variability was high. The developed atazanavir metabolic screening method can now be used for further clinical pharmacological research with this antiretroviral agent.Atazanavir is a commonly used HIV protease inhibitor and is used in combination with other antiretroviral agents for the treatment of HIV infection. Atazanavir has been approved in the European Union for once-daily administration of 300 mg in combination with 100 mg of ritonavir. The protease inhibitor ritonavir is given as a pharmacokinetic booster and increases systemic atazanavir exposure by inhibiting cytochrome P450 enzyme 3A4 (CYP3A4) metabolism in the liver and intestines. In the United States, atazanavir has also been approved in a dose of 400 mg once daily without ritonavir in treatment-naive patients (Swainston Harrison and Scott, 2005).CYP3A4 in the intestinal wall and liver is thought to be the major enzyme responsible for atazanavir biotransformation. Biliary excretion is the main route of excretion of atazanavir. Renal elimination plays a minor role in excreting atazanavir and its metabolites. The main systemically circulating atazanavir metabolites have been described to be mono-oxygenated and dioxygenated products of atazanavir, but their molecular structures have not been released publicly. Other metabolic routes have been proposed to be glucuronidation, N-dealkylation, hydrolysis, hydroxylation, and dehydrogenation Adverse reactions related to atazanavir use are jaundice and QT prolongation. Atazanavir inhibits the UDP-glucuronosyltransferase isoenzyme 1A1 (UGT1A1), the enzyme responsible for bilirubin glucuronidation, causing decreased glucuronide excretion that may result in jaundice. Drug metabolites may contribute to effective...